Controversies in interventional cardiology: eminence, common sense, and evidence

Download the Issue @ a Glance podcast Subscribe to the EHJ Podcast Interventional Cardiology has revolutionized cardiovascular medicine over the last three decades. Starting with a simple balloon 1 and later bare-metal and drug-eluting stents and scaffolds 2 ( Figure 1 ), numerous new devices including occluders for patent foramen ovale 3 and atrial as well as ventricular septal defects, and recently for catheter-based valve implantation, 4 , 5 have been developed and also partly tested in first-in-men studies and randomized trials. In his ESC Lecture ‘ Interventional cardiology, where real life and science do not necessarily meet ’, Bernhard Meier from the University Hospital Bern in Switzerland challenges the concept that evidence-based diagnosis, decision-making, and therapy is and should primarily guide the field. 6 He notes that generating and publishing evidence is a tedious job according to ever new and tightened research practice regulations. 7 Rules will never prevent the typical human behaviour to show new things as being shinier and old things as being dustier than they really are. He continues by discussing examples of misguidance by poorly produced or misinterpreted evidence. Coronary stents, for instance, were first underestimated due to the fact that they were generally used in bailout situations 2 where the outcome remained rather dismal. Then they were overused rather to the detriment of the patient. Now with drug-eluting stents, the overuse persists, but, due to the lower rate of restenosis 8 and stent thrombosis, 9 is no longer a concern. However, the enhanced potential of drug-eluting stents compared with bare-metal stents was poorly exploited for >10 years because of reports that slipped through the net of good review and publication practice to convey the untenable message that bare-metal stents were preferable. 10 Further, Meier believes that the use of fractional flow reserve for decision-making 1,1 , 1,2 has to be questioned. Fixing a lesion today is easier and hardly more complication prone than assessing it with fractional flow reserve. Closure of the patent foramen ovale may never be properly applied, because the collection of the requested evidence takes decades, a follow-up duration that makes research unattractive to physicians and financers. Transarterial aortic valve replacement, finally, is certain eventually to supplant surgical aortic valve replacement. However, Meier suggests that this should have already been accomplished as a logical progression. The adoption of this remarkable breakthrough technology is slowed down by the quest for providing randomized evidence in patients for whom the evidence should rather be derived from already existing studies, and by the quest to triage all these patients in a heart team, meaning also to feed the surgeons although these patients do not really need them. 6 To put this matter into further perspective, the opinion piece is complimented by an editorial comment ‘ Eminence, common sense, and evidence ’ written by Editor-in-Chief Thomas F. Lüscher from the University Hospital Zurich, Switzerland which discusses the provocative concepts of Bernard Meier. 13 Development of coronary intervention over 4 decades. One of the issues discussed by Bernard Meier is further touched on by Fabian Nietlispach and colleagues from the University Hospital in Zurich, Switzerland in the review article ‘ Percutaneous closure of patent foramen ovale: an underutilized prevention? ’ The topic is clinically relevant as paradoxical embolism through a patent foramen ovale is a recognized cause of stroke, and catheter-based closure of a percutaneous patent foramen ovale today is a simple and safe procedure. 14 The debate on patent foramen ovale closure is far from settled, in part due to the fact that the three randomized controlled trials on patent foramen ovale closure vs. medical therapy were negative regarding their primary endpoint; however, as-treated and per-protocol analyses as well as several meta-analyses 3 , 15 report a benefit of patent foramen ovale closure. This again points to the important question of whether in device trials as-treated analysis should be considered solid evidence. Fabian Nietlispach suggests that it should, and that percutaneous closure of a patent foramen ovale is underutilized currently. A patent foramen ovale not only allows a venous thrombus to reach the brain, 16 but also provides mediators in the venous blood to pass to the arterial circulation. Some of these molecules that normally are disposed of during passage of the pulmonary circulation, for instance serotonin, may cause migraine. Heinrich Mattle and colleagues from the University Hospital Bern in Switzerland tested this hypothesis in the randomized PRIMA trial ‘ Percutaneous closure of patent foramen ovale in migraine with aura: a randomized controlled trial ’ . PRIMA was a multicentre, randomized trial to investigate the effect of percutaneous patent foramen ovale closure in patients refractory to medical treatment. 17 A total of 107 patients with migraine with aura and patent foramen ovale who were unresponsive to preventive medications were randomized to patent foramen ovale closure with an Amplatzer occluder or medical treatment, and 83 completed the 12 months follow-up. Both groups were given acetylsalicylic acid 75–100 mg/day for 6 months and clopidogrel 75 mg/day for 3 months. The primary endpoint was reduction in monthly migraine days during months 9–12 after randomization compared with a 3-month baseline phase before randomization. Mean migraine days at baseline were 8 in the closure group and 8.3 in controls. The primary endpoint was therefore negative, with 2.9 less days after patent foramen ovale closure vs. 1.7 days less in the control group. However, according to post-hoc analyses, patent foramen ovale closure significantly reduced migraine with aura attacks and migraine with aura days, and enhanced responder rates. Thus, the authors conclude that in patients with refractory migraine with aura and patent foramen ovale, patent foramen ovale closure did not reduce overall monthly migraine days, but had an effect on migraine with aura days and attacks. The findings are discussed in a critical Editorial by Andreas Luft from the University Hospital Zurich in Switzerland. 18 Sequential optical coherence tomography frames showing the continuum between evaginations and malpposition. Evaginations are marked in light blue and the malapposition (left) in red. From proximal to distal, the first three slides from right show the evolution of an evagination. In the fourth section, two malapposed scaffold struts appear, which reclassify this lesion to malapposition. In contrast, the lesion at 6 o'clock does not contain malapposed struts. This sequence emphasized the importance of frame-by-frame analysis. The most recent developments for coronary intervention are bioabsorbable stents or scaffolds used either in stable patients 19 , 20 or even in those with acute coronary synndromes. 21 , 22 Stent thrombosis, however, seems to be somewhat higher with scaffolds than with regular drug-eluting stents. 23 , 24 Peri-stent coronary evaginations may disturb flow and have been proposed as a possible risk factor for late stent thrombosis. In their manuscript entitled ‘Coronary evaginations and peri-scaffold aneurysms following implantation of bioresorbable scaffolds: incidence, outcome, and optical coherence tomography analysis of possible mechanisms ’, Tommaso Gori and colleagues from the University of Mainz in Germany describe the incidence, predictors, and possible mechanisms of coronary evaginations 12 months following implantation of bioresorbable vascular scaffolds ( Figure 2 ). 25 A total of 102 bioresorbable vascular scaffolds implanted in 90 patients were analysed with angiography and optical coherence tomography 12 months after implantation. Evaginations were identified as any hollow in the luminal vessel contour between well-apposed struts and were classified as major when extending ≥3 mm with a depth ≥10% of the bioresorbable vascular scaffolds diameter. Of the bioresorbable vascular scaffolds, 54% had at least one evagination with a mean volume of 1.9 ± 1.9 mm 3 . Major evaginations were only found in one patient, and in-bioresorbable vascular scaffold aneurysms in three patients. The presence of evaginations was strongly associated with that of malapposition and strut fractures. Peri-strut low intensity areas were present in 53% of the bioresorbable scaffolds with evaginations, but in only 26% of those without it. Their presence was independently associated with the presence, the number, and volume of the evaginations and with the presence of strut fracture. Thus, evaginations detected by optical coherence tomography are relatively common after bioresorbable vascular scaffold implantation, but—as for modern drug-eluting metallic stents—major evaginations are very rare. Optical coherence tomography evidence of immature neointima and strut fractures was associated with more severe development of evaginations. The findings are discussed in an Editorial by Maria D. Radu from the University of Copenhagen in Denmark. 26 The outcome of percutaneous coronary interventions is determined not only by technical, but also by patient-related factors. 27 One rarely discussed co-morbidity has been investigated in the paper entitled ‘ Clinical outcomes of patients with hypothyroidism undergoing percutaneous coronary intervention ’ by Ming Zhang and colleagues from the Mayo Clinic, Rochester, Minnesota. 28 The authors analysed the association between hypothyroidism and major adverse cardiovascular and cerebral events or MACCE in 2430 patients undergoing percutaneous coronary intervention divided into two groups: 686 patients with hypothyroidism defined either as a history of hypothyroidism or a thyroid-stimulating hormone (TSH) ≥5.0 mU/mL, and 1744 individuals with euthyroidism. Patients with hypothyroidism were further categorized as untreated, or those on replacement therapy with adequate and those with inadequate replacement. The risk of MACCE and their constituent parts over 3 years was higher in patients with hypothyroidism compared with those with euthyroidism, with a hazard ratio between 1.28 and 1.62 for its different components. Compared with untreated patients or those with inadequate replacement, adequately treated hypothyroid patients had a lower risk of MACCE, with a hazard ratio of 0.69. Thus, hypothyroidism is associated with a higher incidence of MACCE compared with euthyroidism in patients undergoing percutaneous coronary intervention. Maintaining adequate control on thyroid replacement therapy is beneficial in preventing MACCE. The manuscript is further discussed in an Editorial by Baris Gencer from the Geneva University Hospital in Switzerland. 29 Mean TG, flow velocity and MVR data under resting conditions over the whole cardiac cycle, stratified according to angiographic stenosis severity. With progressive stenosis severity, TG increases, while flow velocity is maintained at a stable level by progressive compensatory reduction of MVR. Curves are fitted by 2nd, 3rd order and fractional polynomials. Our understanding of human coronary physiological behaviour is derived from animal models, but species differences may matter. Furthermore, different physiological coronary parameters may have different clinical value. 30 In their paper ‘ Coronary pressure and flow relationships in humans: phasic analysis of normal and pathological vessels and the implications for stenosis assessment. A report from the Iberian–Dutch–English (IDEAL) collaborators ’, Sukhjinder S. Nijjer and colleagues from the Imperial College London sought to describe physiological behaviour across a large collection of invasive pressure and flow velocity, to provide a better understanding of the relationships between these physiological parameters and to evaluate the rationale for resting stenosis assessment. 31 A total of 567 simultaneous intracoronary pressure and flow velocity assessments from 301 patients were analysed for coronary flow velocity, trans-stenotic gradient, and microvascular resistance. With progressive worsening of stenoses, from unobstructed angiographic normal vessels to those with fractional flow reserve ≤0.50, hyperaemic flow fell significantly from 45 to 19 cm/s in a curvilinear pattern, while resting flow was unaffected by stenosis severity. The trans-stenotic gradient rose with stenosis severity for both rest and hyperaemic measures. Microvascular resistance declined with stenosis severity under resting conditions, but was unchanged at hyperaemia. Thus, with progressive stenosis severity, the trans-stenotic gradient rises. However, while hyperaemic flow falls, resting coronary flow is maintained by compensatory reduction of microvascular resistance, reflecting coronary autoregulation. This supports the translation of coronary physiological concepts derived from animals to patients with coronary artery disease and suggests that resting pressure indices can be used to detect the haemodynamic significance of coronary artery stenoses. The manuscript is accompanied by a thought-provoking Editorial by Christian Seiler from the University Hospital Berne, Switzerland. 32 The editors hope that this issue of the European Heart Journal will be of interest to its readers.