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Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

The Academic Research Consortium (ARC)-2 initiative revisited the clinical and angiographic end point definitions in coronary device trials, proposed in 2007, to make them more suitable for use in clinical trials that include increasingly complex lesion and patient populations and incorporate novel devices such as bioresorbable vascular scaffolds. In addition, recommendations for the incorporation of patient-related outcomes in clinical trials are proposed. Academic Research Consortium-2 is a collaborative effort between academic research organizations in the United States and Europe, device manufacturers, and European, US, and Asian regulatory bodies. Several in-person meetings were held to discuss the changes that have occurred in the device landscape and in clinical trials and regulatory pathways in the last decade. The consensus-based end point definitions in this document are endorsed by the stakeholders of this document and strongly advocated for clinical trial purposes. This Academic Research Consortium-2 document provides further standardization of end point definitions for coronary device trials, incorporating advances in technology and knowledge. Their use will aid interpretation of trial outcomes and comparison among studies, thus facilitating the evaluation of the safety and effectiveness of these devices.

Aims: The CAPTIM (Comparison of primary Angioplasty and Pre-hospital fibrinolysis In acute Myocardial infarction) study found no evidence that a strategy of primary angioplasty was superior in terms of 30-day outcomes to a strategy of pre-hospital fibrinolysis with transfer to an interventional facility in patients managed early at the acute phase of an acute myocardial infarction. The present analysis was designed to compare both strategies at 5 years., Methods and Results: The CAPTIM study included 840 patients managed in a pre-hospital setting within 6 h of an acute ST-segment elevation myocardial infarction. Patients were randomized to either a primary angioplasty (n = 421) or a pre-hospital fibrinolysis (rt-PA) with immediate transfer to a centre with interventional facilities (n = 419). Long-term follow-up was obtained in blinded fashion from 795 patients (94.6%). Using an intent-to-treat analysis, all-cause mortality at 5 years was 9.7% in the pre-hospital fibrinolysis group when compared with 12.6% in the primary angioplasty group [HR 0.75 (95% CI, 0.50-1.14); P = 0.18]. For patients included within 2 h, 5 year mortality was 5.8% in the pre-hospital fibrinolysis group when compared with 11.1% in the primary angioplasty group [HR 0.50 (95% CI, 0.25-0.97); P = 0.04], whereas it was, respectively, 14.5 and 14.4% in patients included after 2 h [HR 1.02, (95% CI 0.59-1.75), P = 0.92]., Conclusion: The 5-year follow-up is consistent with the 30-day outcomes of the trial, showing similar mortality for primary percutaneous coronary intervention and a policy of pre-hospital lysis followed by transfer to an interventional center. In addition, for patients treated within 2 h of symptom onset, 5-year mortality was lower with pre-hospital lysis.

Aims: To determine the adjunctive value of CT coronary angiography (CTCA) in the diagnostic work-up of patients with typical angina pectoris., Methods and Results: CTCA was performed in 62 consecutive patients (45 male, mean age 58.8 +/- 7.7 years) with typical angina undergoing diagnostic work-up including exercise-ECG and conventional coronary angiography. Only patients with sinus heart rhythm and ability to breath hold for 20 s were included. Patients with initial heart rates >/=70 beats/min received beta-blockers. We determined the post-test likelihood ratios, to detect or exclude patients with significant (>/=50% lumen diameter reduction) stenoses, of exercise-ECG and CTCA separately, and of CT performed after exercise-ECG testing. The prevalence of patients with significant coronary artery disease (CAD) was 74%. Positive and negative likelihood ratios for exercise-ECG were 2.3 [95% confidence interval (CI): 1.0-5.3] and 0.3 (95% CI: 0.2-0.7) and for CTCA 7.5 (95% CI: 2.1-27.1) and 0.0 (95% CI: 0.0-8), respectively. CTCA increased the post-test probability of significant CAD after a negative exercise-ECG from 58 to 91%, and after a positive exercise-ECG from 89 to 99%, while CT correctly identified patients without CAD (probability 0%)., Conclusion: Non-invasive CTCA is a potentially useful tool, in the diagnostic work-up of patients with typical angina pectoris, both to detect and to exclude significant CAD.

Aims: Endothelial dysfunction has been related both to progression of atherosclerotic disease and to future cardiovascular events. We assessed local epicardial endothelial function 6 months after sirolimus-eluting stent (SES) or bare metal stent (BS) implantation., Methods and Results: In 12 patients (seven SES, five BS), endothelium-dependent vasomotion of a coronary segment 15 mm in length, starting 2 mm distal to the stent, was assessed with quantitative coronary angiography immediately after the procedure and at 6 months follow-up, after intracoronary infusion of acetylcholine. Intravascular ultrasound (IVUS) was performed and coronary flow reserve (CFR) assessed in all patients. At follow-up significant vasoconstriction was seen in SES (median 32% diameter reduction from baseline) but not in BS (median 2% reduction) patients after acetylcholine infusion (P=0.03 for SES vs. BS); endothelium-independent vasodilatation to nitrates did not differ significantly between groups (20% SES, 5% BS, P=0.14). IVUS revealed no late unhealed dissections and CFR was comparable between groups (SES 3.1 vs. BS 3.2, n.s.)., Conclusion: SES implantation may have an adverse effect on local endothelium-dependent vasomotor responses compared with BS implantation at 6 months. Long-term clinical consequences of this observation are still unknown.

Aims: To evaluate, in patients referred for elective percutaneous coronary revascularization (PCR) without heparin pre-treatment, the relationship between baseline serum levels of the angiogenic growth factors, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and clinical outcome., Methods and Results: In 488 consecutive patients undergoing elective coronary angioplasty, hsC-reactive protein, HGF, and VEGF levels were measured before heparin administration. The primary endpoint, a composite of death and myocardial infarction, occurred in 44 patients at a median follow-up of 14.9 months. At baseline, VEGF levels were related to C-reactive protein levels and inversely related to age; HGF levels were related to C-reactive protein levels, diabetes, and recent clinical instability. In the univariate analysis, HGF had a significant positive relationship (P=0.003) with the primary endpoint. A similar trend was observed for VEGF (P=0.11). The only three variables significantly associated with the primary endpoint in the multivariable Cox model were HGF (P=0.004), C-reactive protein (P=0.007), and diabetes (P=0.04)., Conclusion: Our results demonstrate that in patients, without heparin pre-treatment, referred for PCR, a high serum level of HGF is an independent predictor of clinical events during follow-up and is correlated with other surrogate measures of the activity of atherosclerosis.

Aims: To compare, by meta-analytical techniques, the clinical impact of bare-metal stenting vs. balloon angioplasty for the treatment of lesions in small coronary arteries., Methods and Results: We included trials with random allocation and prospective comparison of angioplasty vs. stenting, reference vessel diameter<3 mm, and follow-up>or=6 months. Random effect odds ratios (OR) for death, myocardial infarction (MI), repeat revascularization (RR), and major adverse cardiac events (MACEs) were computed. In a pre-specified subgroup analysis, we compared stenting with optimal (post-procedural stenosis<20%) and suboptimal (>20%) angioplasty. Thirteen studies (4383 patients) were selected. No differences were found in terms of death and MI, while MACEs, mainly driven by RR, were significantly less common after stenting (17.6%) than after angioplasty (22.7%), OR 0.71 (0.57-0.90). Heterogeneity among trials was present. When considering only optimal angioplasty, MACE rates were homogeneously similar, 17.9 vs. 21.1%, OR 0.86 (0.66-1.11). If angioplasty were suboptimal, MACEs were significantly more common after angioplasty (24%) than after stenting (17.3%), OR 0.62 (0.44-0.88)., Conclusion: Stenting is superior to balloon angioplasty for the treatment of small vessels, in particular after suboptimal angioplasty. However, MACE and RR rates remain high after stenting, and the advantage of stent over angioplasty is moderate. An optimal balloon angioplasty strategy (with provisional stenting) may achieve results not inferior to routine stenting.

Objectives: We hypothesized that percutaneous transluminal coronary angioplasty performed on coronary stenoses that have demonstrated rapid angiographic progression would be associated with a high risk of restenosis., Background: High rates of restenosis have been documented after percutaneous transluminal coronary angioplasty of unstable lesions and of lesions that recur rapidly after a successful initial angioplasty. This suggests that the "activity' of the plaque at the time of angioplasty may be an important factor determining the risk of restenosis., Methods: In our institution we recommend angiographic follow-up for all patients with successful percutaneous transluminal coronary angioplasty. In this way we identified 86 consecutive patients who, at the time of angiographic follow-up had not developed restenosis at the dilated site, but required a further percutaneous transluminal coronary angioplasty at a different site. (which was successful). Based on quantitative angiographic measurements, 45 of these lesions (rapidly progressive lesions) had significantly increased in severity in the interval between the two angiograms (7.7 +/- 3.3 months) while 41 (stable lesions) had not. Rapid progression was defined as a > 0.4 mm decrease in minimal lumen diameter between initial angiography and percutaneous transluminal coronary angioplasty. All 86 patients had further angiographic follow-up 6 months later., Results: Baseline clinical and angiographic variables were similar in both groups except that a higher proportion of patients in the rapid progression group had unstable angina (20% vs 5%; P < 0.05). Late loss during follow-up did not differ statistically between groups (0.31 mm) and minimal lumen diameter at follow-up was also similar (stable lesion group = 1.40 +/- 0.48 mm; rapidly progressive lesion group = 1.30 +/- 0.59 mm). The loss index (late loss divided by acute gain) was also similar in both groups (0.45 +/- 0.52 in the stable lesion group, 0.37 +/- 0.76 in the rapidly progressive lesion group). A strong correlation between acute gain and late loss was observed in the stable lesion group (r = 0.61; P < 0.0001); by contrast, there was no relationship between these two variables in the rapidly progressive lesion group (r = 0.20; P = 0.19)., Conclusions: Percutaneous transluminal coronary angioplasty in patients with unstable angina or with early recurrence after a first percutaneous transluminal coronary angioplasty is associated with an increased risk of restenosis. By contrast, this study shows that angiographic instability, as evidenced by rapid stenosis progression, has no deleterious effect on the occurrence of restenosis. Percutaneous transluminal coronary angioplasty thus appears as a reasonable therapeutic option for coronary stenoses that have demonstrated rapid angiographic progression in the months prior to the procedure.

Objective: To describe the morphological changes occurring in the months following percutaneous transluminal coronary angioplasty (PTCA) of unstable plaques., Background: Coronary angioscopy is a relatively new technique to assess plaque morphology. Previous angioscopic studies have shown that unstable coronary lesions are characterized by complex morphology, evidence of plaque rupture, and intraluminal thrombi. No serial angioscopic studies have investigated the effects of PTCA on plaque morphology at such lesions., Methods: We studied 15 patients who underwent successful PTCA for an unstable coronary syndrome (unstable angina: n = 5; recent myocardial infarction: n = 10). Angioscopy was performed immediately before PTCA in 14 patients, immediately after PTCA in 13 patients, and at follow-up (225 +/- 62 days after PTCA) in all patients., Results: Pre-PTCA, plaque morphology was defined as complex in 18%, ulcerated in 27%; the vessel was totally occluded in 18% of cases. Plaque colour was yellow in 75% of patients. A thrombus was identified at the lesion site in 71% of patients. Immediately post-PTCA, small surface disruptions and dissections were observed in 62% of patients. Plaque colour was yellow in 85% of cases. Seventy-seven percent of patients had an angioscopically visible thrombus at the PTCA site. At follow-up, however, plaque shape was almost uniformly classified as smooth concentric (93%); plaque colour was white in 93%; no thrombus was observed., Conclusions: These results demonstrate the healing of unstable plaques in the months following PTCA. The angioscopic appearance at 6 months is that of a stable plaque (smooth concentric, white, without thrombus). Whether this stable angioscopic appearance predicts long-term clinical stability remains to be determined.

Intravascular metallic stents are increasingly used in the non-surgical management of coronary atherosclerosis. Despite intensive anticoagulation, subacute stent thrombosis, which usually has serious clinical consequences, and major haemorrhagic complications remain major problems after stent implantation. In addition, conventional management with anticoagulant therapy requires prolonged hospitalization. In a prospective multicentre study, we investigated the efficacy of a combination of two antiplatelet agents, ticlopidine 500 mg daily and aspirin 200 mg daily, without oral anticoagulation after stent implantation. Since November 1993, 529 consecutive patients, in whom 545 vessels were successfully stented with conventional (non-heparin coated) stents have been enrolled. Stenting was performed as a bailout procedure for failed angioplasty in 112 patients, for a suboptimal result after angioplasty in 314 patients, and electively in the remaining 103 patients. Coronary events related, or possibly related, to stent thrombosis occurred in 5.4% of patients stented as a bailout procedure and in 1.8% of patients stented for a suboptimal result. Serious bleeding complications occurred in 5.4% of patients stented as a bailout procedure and 1.5% of patients stented for a suboptimal result. Neither stent thrombosis nor serious bleeding complications were seen in patients stented electively. Ticlopidine therapy was discontinued in 1.9% of patients due to neutropenia (0.6%) or rash (1.3%). Mean hospital stay decreased from 6.16 +/- 2.14 days to 4.2 +/- 2.15 days during the study period. A combination of two antiplatelet agents can be employed in the vast majority of patients after coronary stent implantation. Subacute stent thrombosis rates and bleeding complications compare favourably with those reported using conventional therapy and the duration of hospitalization is reduced.

Objective: Multiple studies have been designed to analyse restenosis angiographically but few have studied the vasoreactivity of coronary segments subjected to angioplasty a few months before. In the present study we analysed, with use of quantitative angiography, the vasoreactivity of previously dilated segments to graded doses of ergonovine and of isosorbide dinitrate., Patients: Fifty consecutive patients undergoing follow-up angiography 6 months after a single coronary angioplasty procedure were studied., Results: The vasoconstrictor response at dilated segments (-19.3 +/- 3.0%) was significantly greater than at control proximal and distal sites in dilated (-7.3 +/- 1.1%, -11.0 +/- 2.9%) and non-dilated (-9.1 +/- 1.3%, -8.3 +/- 2.2%) vessels for the lowest dose of ergonovine (100 micrograms). The constrictor response to 100 micrograms ergonovine (-20.2 +/- 5.3%) at restenosed segments (> 50% stenosis, n = 18) was similar to that (-18.8 +/- 3.8%) at non-restenosed sites (n = 32). In contrast, the degree of constrictor response was similar in all segments including dilated segments for the highest dose of ergonovine used. All segments dilated significantly after intracoronary injection of isosorbide dinitrate., Conclusion: Our results demonstrate hypersensitivity of the dilated site to ergonovine 6 months after angioplasty at both restenosed and non-restenosed sites. This response may reflect partial dysfunction of endothelium that has regenerated after injury or hypersensitivity of vascular smooth muscle cells at the site of arterial injury.

The major disadvantage of using percutaneous transluminal coronary angioplasty to treat patients with atherosclerotic coronary disease is the frequent occurrence of restenosis after an initially successful procedure. Studies in animals and histological observations in man have demonstrated that restenosis is characterized by neointimal hyperplasia due to smooth muscle cell proliferation and to the synthesis of extracellular matrix. Improvements in technology or pharmacological interventions have had no significant impact on the rate of restenosis. In spite of our increased understanding of the molecular mechanisms of restenosis. no effective treatment is available at the present time. Gene therapy, which has produced encouraging initial results in experimental models, may provide a solution in the medium term.

Clinical, exercise, and angiographic variables, and long-term follow-up were compared in patients, who, during maximal Bruce exercise testing after a first acute myocardial infarction (AMI), had positive responses to exercise testing (n = 116, 38% of 303) with (n = 23, group I) or without (n = 93, group II) angina. Group I patients more often (52 vs 19%, P < 0.001) had a history of pre-infarction angina. Group II had a greater proportion (75 vs 52%, P < 0.05) of inferior wall AMI, whereas group I had a greater proportion (30 vs 19%, P < 0.01) of non-Q wave AMI. Total exercise duration was significantly (P < 0.01) longer in group II (7.6 +/- 3.2 vs 5.5 +/- 3.1 min). Maximal exercise heart rate (144 +/- 22 vs 133 +/- 21, beats.min-1 P < 0.05) was also higher in group II. A greater proportion of group II patients (37 vs 9%, P < 0.05) had single-vessel disease, whereas multivessel disease was more common (91 vs 63%, P < 0.03) in group I. Left ventricular function was similar in both groups. During follow-up (48 +/- 22 months) the incidence of cardiac death (group I, 3.3%, group II, 4.8%), of recurrent infarction (group I, 4.8%, group II 3.3%), and of revascularization procedures (group I, 28.5%, group II, 19.8%) were similar in both groups. Although asymptomatic exercise-induced ischaemia was associated with better exercise performance and less extensive coronary disease than symptomatic ischaemia, it had the same long-term prognostic implications.

Activation of potassium channels induces relaxation of vascular smooth muscle, and experimental studies have demonstrated that potassium channel activators have potent coronary vasodilator properties. In humans, nicorandil, a potassium channel blocker, causes vasodilatation not only in angiographically normal segments but also at sites of dynamic coronary stenosis, where coronary spasm has been provoked by methylergometrine as well as at sites of spontaneous spasm. The efficacy of nicorandil in relieving ergometrine-induced spasm is comparable to that of nifedipine. Oral administration of nicorandil significantly reduces the frequency of anginal episodes in patients with vasospastic angina, and either as monotherapy, or in conjunction with other agents is a novel therapeutic option in patients with vasospastic angina.

This study analyses the immediate outcome and the risk of recurrent restenosis in patients who, at the time of repeat coronary angioplasty for a first restenosis, had unstable (n = 50), 19%) or stable (n = 218, 81%) angina. Successful angioplasty was accomplished in 250 (93%) patients, 222 (89%) of whom had follow-up angiography. Mean time from initial to repeat angioplasty was shorter (P = 0.0002) and angiographic evidence of thrombus was commoner (P = 0.0001) in the unstable group. Major complications (coronary artery bypass grafting or myocardial infarction) were more frequent (P < 0.01) in the unstable group (6% vs 0.5%); no procedure-related deaths occurred. The angiographic rate of restenosis was significantly higher in the unstable group (61% vs 43%, P < 0.05). Despite this high rate of recurrent restenosis, most of the patients in both groups were either asymptomatic or had atypical chest pain at follow-up. Repeat coronary angioplasty, in patients with unstable angina, has a high primary success rate but a higher risk of acute complications than in patients with stable angina. The angiographic rate of restenosis was significantly higher in unstable than in stable patients; however, the clinical status of most patients was improved at follow-up.