Carl E. Schotborgh

Fractional flow reserve, absolute and relative coronary blood flow velocity reserve in relation to the results of technetium-99m sestamibi single-photon emission computed tomography in patients with two-vessel coronary artery disease.

OBJECTIVES We sought to perform a direct comparison between perfusion scintigraphic results and intracoronary-derived hemodynamic variables (fractional flow reserve [FFR]; absolute and relative coronary flow velocity reserve [CFVR and rCFVR, respectively]) in patients with two-vessel disease. BACKGROUND There is limited information on the diagnostic accuracy of intracoronary-derived variables (CFVR, FFR and rCFVR) in patients with multivessel disease. METHODS Dipyridamole technetium-99m sestamibi (MIBI) single-photon emission computed tomography (SPECT) was performed in 127 patients. The presence of reversible perfusion defects in the region of interest was determined. Within one week, angiography was performed; CFVR, rCFVR and FFR were determined in 161 coronary lesions after intracoronary administration of adenosine. The predictive value for the presence of reversible perfusion defects on MIBI SPECT of CFVR, rCFVR and FFR was evaluated by the area under the curve (AUC) of the receiver operating characteristics curves. RESULTS The mean percentage diameter stenosis was 57% (range 35% to 85%), as measured by quantitative coronary angiography. Using per-patient analysis, the AUCs for CFVR (0.70 +/- 0.052), rCFVR (0.72 +/- 0.051) and FFR (0.76 +/- 0.050) were not significantly different (p = NS). The percentages of agreement with the results of MIBI SPECT were 76%, 78% and 77% for CFVR, rCFVR and FFR, respectively. Per-lesion analysis, using all 161 measured lesions, yielded similar results. CONCLUSIONS The diagnostic accuracy of three intracoronary-derived hemodynamic variables, as compared with the results of perfusion scintigraphy, is similar in patients with two-vessel coronary artery disease. Cut-offvalues of 2.0 for CFVR, 0.65 for rCFVR and 0.75 for FFR can be used for clinical decision-making in this patient cohort. Discordant results were obtained in 23% of the cases that require prospective evaluation for appropriate patient management.

Fractional Flow Reserve–Guided Multivessel Angioplasty in Myocardial Infarction

BACKGROUND In patients with ST‐segment elevation myocardial infarction (STEMI), the use of percutaneous coronary intervention (PCI) to restore blood flow in an infarct‐related coronary artery improves outcomes. The use of PCI in non‐infarct‐related coronary arteries remains controversial. METHODS We randomly assigned 885 patients with STEMI and multivessel disease who had undergone primary PCI of an infarct‐related coronary artery in a 1:2 ratio to undergo complete revascularization of non‐infarct‐related coronary arteries guided by fractional flow reserve (FFR) (295 patients) or to undergo no revascularization of non‐infarct‐related coronary arteries (590 patients). The FFR procedure was performed in both groups, but in the latter group, both the patients and their cardiologist were unaware of the findings on FFR. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, revascularization, and cerebrovascular events at 12 months. Clinically indicated elective revascularizations performed within 45 days after primary PCI were not counted as events in the group receiving PCI for an infarct‐related coronary artery only. RESULTS The primary outcome occurred in 23 patients in the complete‐revascularization group and in 121 patients in the infarct‐artery‐only group that did not receive complete revascularization, a finding that translates to 8 and 21 events per 100 patients, respectively (hazard ratio, 0.35; 95% confidence interval [CI], 0.22 to 0.55; P<0.001). Death occurred in 4 patients in the complete‐revascularization group and in 10 patients in the infarct‐artery‐only group (1.4% vs. 1.7%) (hazard ratio, 0.80; 95% CI, 0.25 to 2.56), myocardial infarction in 7 and 28 patients, respectively (2.4% vs. 4.7%) (hazard ratio, 0.50; 95% CI, 0.22 to 1.13), revascularization in 18 and 103 patients (6.1% vs. 17.5%) (hazard ratio, 0.32; 95% CI, 0.20 to 0.54), and cerebrovascular events in 0 and 4 patients (0 vs. 0.7%). An FFR‐related serious adverse event occurred in 2 patients (both in the group receiving infarct‐related treatment only). CONCLUSIONS In patients with STEMI and multivessel disease who underwent primary PCI of an infarct‐related artery, the addition of FFR‐guided complete revascularization of non‐infarct‐related arteries in the acute setting resulted in a risk of a composite cardiovascular outcome that was lower than the risk among those who were treated for the infarct‐related artery only. This finding was mainly supported by a reduction in subsequent revascularizations. (Funded by Maasstad Cardiovascular Research and others; Compare‐Acute ClinicalTrials.gov number, NCT01399736.)

C-reactive protein and coronary events following percutaneous coronary angioplasty

Abstract Purpose We investigated the associations between baseline C-reactive protein levels in patients undergoing percutaneous coronary angioplasty and death, nonfatal myocardial infarction, and repeat revascularization during 14 months of follow-up. Methods In a single-center, prospective, cohort study, plasma levels of C-reactive protein were measured in 1458 consecutive patients undergoing elective or urgent coronary angioplasty. Patients were followed at 12 to 14 months for the occurrence of death, nonfatal myocardial infarction, and repeat revascularization. Results The incidence of death or myocardial infarction was 6.1% (44/716) in patients with an increased C-reactive protein level (>3 mg/L) and 1.5% (11/742) in patients with a normal level (relative risk [RR] = 4.4; 95% confidence interval [CI]: 2.2 to 8.5; P P = 0.0001). The incidence of repeat revascularization was similar in patients with or without an increased C-reactive protein level (23% [168/716] vs. 22% [163/742], P = 0.54). Statin therapy at the time of the procedure was associated with a lower mean (± SD) C-reactive protein level (5.8 ± 9.7 mg/L vs. 7.2 ± 12.1 mg/L, P = 0.02), but was not associated with the risk of death, nonfatal myocardial infarction, and repeat revascularization during follow-up. Conclusion An increased C-reactive protein level is an independent prognostic indicator for the occurrence of death or nonfatal myocardial infarction following coronary angioplasty, but is not associated with the need for repeat revascularization.

Sulfonylurea derivatives in cardiovascular research and in cardiovascular patients

Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). In the beta-cell sulfonylureas act by blocking ATP-sensitive potassium channels (K.ATP channels). In several organ systems, including the cardiovascular system, sulfonylurea receptors and functional K.ATP channels have been identified. In the heart their role is not clear: an endogenous cardioprotective effect has been suggested. There is no doubt that K.ATP channels are effectively blocked by sulfonylureas. In the last decade sulfonylureas have been widely used as a pharmacological tool in experimental (cardiac) research. Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. However, other membrane currents are affected as well. In addition, myocardial metabolism is modified by sulfonylurea pretreatment. Hence, it should seriously be questioned whether these drugs are suitable in assessing involvement of cardiac K.ATP channels in, for example, ischemia-related events. The detrimental effects of sulfonylureas in experimental studies on myocardial ischemia have led to speculation whether the widespread use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease, should be reconsidered. However, a review of the clinical literature reveals that the most consistent finding is a lower incidence of ventricular arrhythmias associated with the use of glibenclamide, while no excess mortality has been shown for this agent in NIDDM with ischemic heart disease. Despite some direct effects on systemic and coronary vasculature, there are, at present, no firm clinical data on the basis of which sulfonylurea derivatives should be withheld from the cardiac patient.

Impact of Coronary Microvascular Function on Long-Term Cardiac Mortality in Patients With Acute ST-Segment–Elevation Myocardial Infarction

Background—Microvascular function is increasingly being recognized as an important marker of risk in coronary artery disease, and may be accurately assessed by intracoronary Doppler flow velocity measurements. In the setting of ST-segment–elevation myocardial infarction there are limited data regarding the prognostic value of microvascular function in both infarct-related and reference coronary arteries for long-term clinical outcome. We sought to determine the prognostic value of microvascular function, as assessed by Doppler flow velocity measurements, for cardiac mortality after primary percutaneous coronary intervention for acute ST-segment–elevation myocardial infarction. Methods and Results—Between April 1997 and August 2000, we included 100 consecutive patients with a first anterior wall ST-segment–elevation myocardial infarction. Immediately after primary percutaneous coronary intervention, intracoronary Doppler flow velocity was measured in the infarct-related artery, to determine coronary flow velocity reserve (CFVR), diastolic deceleration time, and the presence of systolic retrograde flow, as well as in a reference vessel to determine reference vessel CFVR. The primary end point was cardiac mortality at 10-year follow-up. Complete follow-up was obtained in 94 patients (94%). At 10-year follow-up, cardiac mortality amounted to 14%. Cardiac mortality amounted to 5% when reference vessel CFVR was normal (≥2.1), in contrast to 31% when abnormal (<2.1; P=0.001). Reference vessel CFVR <2.1 was associated with a 4.09 increase in long-term cardiac mortality hazard after multivariate adjustment for identified predictors for cardiac mortality (hazard ratio, 4.09; 95% confidence interval, 1.18–14.17; P=0.03) Conclusions—Microvascular dysfunction, measured by reference vessel CFVR determined after primary percutaneous coronary intervention for acute anterior wall ST-segment–elevation myocardial infarction is associated with a significantly increased long-term cardiac mortality.

Comparison of 3 biodegradable polymer and durable polymer-based drug-eluting stents in all-comers (BIO-RESORT): Rationale and study design of the randomized TWENTE III multicenter trial

AIM To evaluate the safety and efficacy of 2 novel drug-eluting stents (DES) with biodegradable polymer-based coatings versus a durable coating DES. METHODS AND RESULTS BIO-RESORT is an investigator-initiated, prospective, patient-blinded, randomized multicenter trial in 3540 Dutch all-comers with various clinical syndromes, requiring percutaneous coronary interventions (PCI) with DES implantation. Randomization (stratified for diabetes mellitus) is being performed in a 1:1:1 ratio between ORSIRO sirolimus-eluting stent with circumferential biodegradable coating, SYNERGY everolimus-eluting stent with abluminal biodegradable coating, and RESOLUTE INTEGRITY zotarolimus-eluting stent with durable coating. The primary endpoint is the incidence of the composite endpoint target vessel failure at 1 year, consisting of cardiac death, target vessel-related myocardial infarction, or clinically driven target vessel revascularization. Power calculation assumes a target vessel failure rate of 8.5% with a 3.5% non-inferiority margin, giving the study a power of 85% (α level .025 adjusted for multiple testing). The impact of diabetes mellitus on post-PCI outcome will be evaluated. The first patient was enrolled on December 21, 2012. CONCLUSIONS BIO-RESORT is a large, prospective, randomized, multicenter trial with three arms, comparing two DES with biodegradable coatings versus a reference DES with a durable coating in 3540 all-comers. The trial will provide novel insights into the clinical outcome of modern DES and will address the impact of known and so far undetected diabetes mellitus on post-PCI outcome.

Thin composite wire strut, durable polymer-coated (Resolute Onyx) versus ultrathin cobalt–chromium strut, bioresorbable polymer-coated (Orsiro) drug-eluting stents in allcomers with coronary artery disease (BIONYX): an international, single-blind, randomised non-inferiority trial

BACKGROUND During the past decade, many patients had zotarolimus-eluting stents implanted, which had circular shape cobalt-chromium struts with limited radiographic visibility. The Resolute Onyx stent was developed to improve visibility while reducing strut thickness, which was achieved by using a novel composite wire with a dense platinum-iridium core and an outer cobalt-chromium layer. We did the first randomised clinical trial to assess the safety and efficacy of this often-used stent compared with the Orsiro stent, which consists of ultrathin cobalt-chromium struts. METHODS We did an investigator-initiated, assessor-blinded and patient-blinded, randomised non-inferiority trial in an allcomers population at seven independently monitored centres in Belgium, Israel, and the Netherlands. Eligible participants were aged 18 years or older and required percutaneous coronary intervention with drug-eluting stents. After guide wire passage with or without predilation, members of the catheterisation laboratory team used web-based computer-generated allocation sequences to randomly assign patients (1:1) to either the Resolute Onyx or the Orsiro stent. Randomisation was stratified by sex and diabetes status. Patients and assessors were masked to allocated stents, but treating clinicians were not. The primary endpoint was target vessel failure at 1 year, a composite of cardiac death, target-vessel-related myocardial infarction, and target vessel revascularisation, and was assessed by intention to treat (non-inferiority margin 2·5%) on the basis of outcomes adjudicated by an independent event committee. This trial is registered with ClinicalTrials.gov, number NCT02508714. FINDINGS Between Oct 7, 2015, and Dec 23, 2016, 2516 patients were enrolled, 2488 of whom were included in the intention-to-treat analysis (28 withdrawals or screening failures). 1243 participants were assigned to the Resolute Onyx group, and 1245 to the Orsiro group. Overall, 1765 (70·9%) participants presented with acute coronary syndromes and 1275 (51·2%) had myocardial infarctions. 1-year follow-up was available for 2478 (99·6%) patients. The primary endpoint was met by 55 (4·5%) patients in the Resolute Onyx group and 58 (4·7%) in the Orsiro group. Non-inferiority of Resolute Onyx to Orsiro was thus established (absolute risk difference -0·2% [95% CI -1·9 to 1·4]; upper limit of the one-sided 95% CI 1·1%; pnon-inferiority=0·0005). Definite or probable stent thrombosis occurred in one (0·1%) participant in the Resolute Onyx group and nine (0·7%) in the Orsiro group (hazard ratio 0·11 [95% CI 0·01-0·87]; p=0·0112). INTERPRETATION The Resolute Onyx stent was non-inferior to Orsiro for a combined safety and efficacy endpoint at 1-year follow-up in allcomers. The low event rate in both groups suggests that both stents are safe, and the very low rate of stent thrombosis in the Resolute Onyx group warrants further clinical investigation. FUNDING Biotronik and Medtronic.

Bioresorbable Polymer-Coated Orsiro Versus Durable Polymer-Coated Resolute Onyx Stents (BIONYX) : Rationale and design of the randomized TWENTE IV multicenter trial

Aim The aim was to compare in a noninferiority trial the efficacy and safety of 2 contemporary drug‐eluting stents (DESs): a novel, durable polymer‐coated stent versus an established bioabsorbable polymer‐coated stent. Methods and results The BIONYX trial (ClinicalTrials.gov‐no.NCT02508714) is an investigator‐initiated, prospective, randomized, patient‐ and assessor‐blinded, international, multicenter study in all‐comer patients with all types of clinical syndromes and lesions who require percutaneous coronary interventions with DES. Patients at 7 study sites in the Netherlands, Belgium, and Israel were randomly assigned (1:1, stratified for gender and diabetes mellitus) to treatment with the novel, zotarolimus‐eluting, durable polymer‐coated Resolute Onyx stent that has a radiopaque, thin‐strut, CoreWire stent platform versus the sirolimus‐eluting, bioresorbable polymer‐coated Orsiro stent (reference device) that has a very thin‐strut, cobalt‐chromium stent backbone. The primary end point is the 1‐year incidence of the composite clinical end point target vessel failure consisting of cardiac death, target vessel–related myocardial infarction, or clinically indicated target vessel revascularization. A power calculation, assuming a target vessel failure rate of 6.0% (noninferiority margin 2.5%), revealed that 2,470 study patients would give the study 80% power (&agr; level 5%), allowing for up to 3% loss to follow‐up. The first patient was enrolled on October 7, 2015; on December 23, 2016, the last patient entered the study. Conclusions BIONYX is a large‐scale, prospective, randomized, international, multicenter trial comparing a novel DES with durable coating versus a reference DES with biodegradable coating in all‐comers. The study is the first randomized assessment of the Resolute Onyx stent, which is an often‐used DES outside the United States.

Six months versus 12 months dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): randomised, multicentre, non-inferiority trial

Abstract Objective To show that limiting dual antiplatelet therapy (DAPT) to six months in patients with event-free ST-elevation myocardial infarction (STEMI) results in a non-inferior clinical outcome versus DAPT for 12 months. Design Prospective, randomised, multicentre, non-inferiority trial. Setting Patients with STEMI treated with primary percutaneous coronary intervention (PCI) and second generation zotarolimus-eluting stent. Participants Patients with STEMI aged 18 to 85 that underwent a primary PCI with the implantation of second generation drug-eluting stents were enrolled in the trial. Patients that were event-free at six months after primary PCI were randomised at this time point. Interventions Patients that were taking DAPT and were event-free at six months were randomised 1:1 to single antiplatelet therapy (SAPT) (ie, aspirin only) or to DAPT for an additional six months. All patients that were randomised were then followed for another 18 months (ie, 24 months after the primary PCI). Main outcome measures The primary endpoint was a composite of all cause mortality, any myocardial infarction, any revascularisation, stroke, and thrombolysis in myocardial infarction major bleeding at 18 months after randomisation. Results A total of 1100 patients were enrolled in the trial between 19 December 2011 and 30 June 2015. 870 were randomised: 432 to SAPT versus 438 to DAPT. The primary endpoint occurred in 4.8% of patients receiving SAPT versus 6.6% of patients receiving DAPT (hazard ratio 0.73, 95% confidence interval 0.41 to 1.27, P=0.26). Non-inferiority was met (P=0.004 for non-inferiority), as the upper 95% confidence interval of 1.27 was smaller than the prespecified non-inferiority margin of 1.66. Conclusions DAPT to six months was non-inferior to DAPT for 12 months in patients with event-free STEMI at six months after primary PCI with second generation drug-eluting stents. Trial registration Clinicaltrials.gov NCT01459627.

ATP-Sensitive Potassium Channel Openers and Blockers in the Cardiovascular System: Physiology, Pharmacology, and Clinical Effects:

Adenosine triphosphate (ATP)-sensitive potassium chan nels (K.ATP channels), a subclass of potassium channels activated by a low intracellular ATP concentration, have been described in various tissue types, including the heart muscle and vascular smooth muscle. In ventricu lar myocytes, activation of these channels is considered protective, because their activation caused by hypoxia or ischemia results in cell energy preservation. Activa tion of K.ATP channels in vascular smooth muscle cells causes hyperpolarization of the cell membrane, muscle cell relaxation, and vasodilation. Potassium channel openers are pharmacologic activators of K.ATP chan nels. Their protective effects on the ischemic myocar dium and their vasodilating properties have been stud ied extensively. Sulfonylurea derivatives, widely used in the treatment of noninsulin-dependent diabetes melli tus, are considered selective blockers of K.ATP channels and have been used in many experiments to show K.ATP channel involvement. This article focuses on these issues and the clinical effects and potentials of K.ATP channel modulation.