Advances in Clinical Cardiology 2016: A Summary of the Key Clinical Trials

Treatment of unprotected left main coronary artery disease by PCI has increased significantly on the basis of findings from small studies, subgroup analyses, and observational data, but adequately powered studies were awaited. At TCT 2016, findings of two key trials were presented.

EXCEL (Evaluation of Xience versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) randomized 1905 patients with significant left main disease (Syntax 32 or lower) to PCI with Xience everolimus-eluting stents or to CABG (voronary artery bypass grafting) [20]. The incidence of the primary composite endpoint of death, MI, and stroke at a median of 3 years was similar with PCI and CABG (15.4% vs 14.7%; p = 0.02 for non-inferiority). PCI was associated with lower death, MI, or stroke at the earlier time point of 30 days (4.9% vs 7.9%; p = 0.008 for superiority) and a lower incidence of bleeding, arrhythmia, renal failure, and infection. Ischemia-driven revascularization was more common with PCI at 3 years (12.6% vs 7.5%; p < 0.001) but thrombosis (definite stent thrombosis or graft occlusion) was less common with PCI (0.7% vs 5.4%; p < 0.001).

The NOBLE (Nordic-Baltic-British left main revascularisation) study randomized (1:1) 1201 patients with significant left main disease and no more than three non-left main, non-complex lesions to PCI (n = 598) or CABG (n = 603). The incidence of the primary endpoint of death, MI (excluding procedural MI), stroke, and revascularization up to 5 years (median 3 years) was higher in PCI than CABG [121 (29%) vs 81(19%) patients; p = 0.0066] but there was no significant difference in mortality [21]. Need for revascularization was more common with PCI than CABG (16% vs 10%; p = 0.032) but this was driven by de novo, non-left main lesions. Unlike the Syntax trial left main subset [22], in NOBLE, the baseline Syntax score did not predict outcome for those undergoing PCI and an unexpectedly high event rate was seen in those undergoing PCI in the low (1–22) Syntax subgroup. Further detailed analysis is planned to evaluate if this finding was due to specific anatomic subsets, specific PCI strategies, or other factors [23].

Although EXCEL and NOBLE outcomes appear disparate, this is likely due to differences in trial design. EXCEL included large procedural MI (creatine kinase MB greater than ten times upper normal) within the definition of MI, whereas NOBLE excluded procedural MI. EXCEL had a shorter follow-up than NOBLE which may be relevant since differences favoring CABG emerge between 3 and 5 years. EXCEL implanted only second-generation DES, whereas NOBLE included 11% of patients with first-generation DES before the new generation Biomatrix stent was mandated. After adjusting for these differences, the trial outcomes appear similar and in keeping with prior CABG vs PCI trial data.

A criticism of some studies is that patients undergoing study CABG have higher than usual rates of bilateral internal thoracic [mammary] artery (ITA) grafting which might be associated with better patency. The Arterial Revascularization Trial (ART) enrolled 3102 patients and randomly assigned (1:1) to single (n = 1554) or bilateral (n = 1548) ITA grafting. At 5 years, the rate of death (8.7% vs 8.4%; p = 0.77) and composite of death from any cause, MI, or stroke (12.2% vs 12.7%; p = 0.69) did not differ, but rates of sternal wound complications were higher with bilateral ITA grafts (3.5% vs 1.9%; p = 0.005) [24]. However, longer follow-up is needed to evaluate the effect of presumed long-term patency of ITA vs vein grafting on clinical outcomes and 10-year follow-up is planned.

A short duration of DAPT post PCI is desirable in many patients including those at high bleeding risk. The BioFreedom stent facilitates a short 1-month course of DAPT since, instead of having a polymer layer, it has a novel microporous abluminal surface (Fig. 2) which enables controlled release of Biolimus A9 achieving therapeutic local tissue concentrations for 28 days post implantation [25]. The LEADERS-FREE trial randomized 2466 high-bleeding-risk patients to receive the BioFreedom drug-coated stent (DCS) or a bare metal stent (BMS) followed by 1-month DAPT. At 2-year follow-up BioFreedom was associated with a 46% reduction in the primary efficacy endpoint of clinically driven TLR (6.8% vs 12.0% patients, respectively; hazard ratio 0.54; 95% CI 0.41–0.72; p < 0.0001) and a 20% reduction in the primary safety endpoint of cardiac death, stent thrombosis, or MI (12.6% DCS vs 15.3% BMS patients; HR 0.80; 95% CI 0.64–0.99; p = 0.039) (Fig. 3) [26]. Current use of BMS is now largely confined to patients thought likely to require short courses of DAPT and LEADERS FREE suggests that drug-coated stents will likely replace BMS for this indication also. The LEADERS FREE II registry is ongoing evaluating outcomes of BioFreedom in a combined US and global cohort.

For stents requiring a polymer for drug elution, use of a biodegradable polymer may reduce risk of very late stent thrombosis vs a permanent polymer [27]. The ultra-thin strut (60 µm) cobalt-chromium Orsiro stent (Biotronik, Berlin, Germany) which has a passive silicon carbide layer overlaid by a biodegradable PLLA polymer releasing sirolimus was previously found to have similar overall clinical outcomes vs Xience (Abbott, Illinois, USA) and superior outcomes in the STEMI subgroup [28]. PCI in chronic total occlusion (CTO) is another challenging subgroup, typically associated with longer stent length and higher TLR. PRISON IV (Bioresorbable polymer-based sirolimus-eluting stent versus a durable polymer-based everolimus-eluting stent in patients with coronary artery chronic total occlusions) randomized 330 patients with successfully crossed chronic total occlusions to Orsiro vs Xience. Surprisingly, Orsiro was associated with greater in-segment late lumen loss (0.13 vs 0.02 mm; primary non-inferiority endpoint not met) and more frequent binary restenosis (8.0% vs 2.1%; p = 0.028) at 9 months [29]. However, PRISON IV was underpowered to evaluate incidence of very late stent thrombosis and further studies are warranted.

The Absorb stent, a bioresorbable vascular scaffold (BVS), fully resorbs in 3 years. It was hoped the absence of a permanent stent would be associated with improved coronary vasomotion (reported to be impaired after first-generation DES) [30] and reduced risk of very late stent thrombosis. Significant expectation thus awaited findings of ABSORB II (Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent) in which 501 patients with one to two non-complex lesions undergoing PCI were randomized (2:1) to BVS vs Xience. At 3 years, disappointingly there was no significant difference in the co-primary endpoint of vasomotor reactivity after nitroglycerin, BVS had greater late lumen loss (0.37 vs 0.25 mm; p _{non-inferiority} = 0.78), and of concern in the BVS group were eight definite scaffold thromboses (one acute, one subacute, six very late) and one probable late scaffold thrombosis vs zero with Xience (p = 0.0331) [31]. ABSORB II raised concerns that long duration (2–3 years) DAPT may be necessary after BVS and suggested that further design iteration and clinical study are required before BVS is considered suitable for widespread use.

Diagnostic PCI is usually angiographically guided alone, although it is recognized that intravascular ultrasound (IVUS) guidance may be associated with decreased MACE. While optical coherence tomography (OCT) produces superior resolution (Fig. 4), equivocal or superior data guiding PCI is lacking. ILUMIEN III (OPTIMIZE PCI) sought to clarify this by randomizing (1:1:1) 450 patients to OCT, IVUS, or angiography with final OCT acquisitions for the primary endpoint of post-PCI minimal stent area (MSA). OCT guidance was non-inferior to IVUS guidance but not superior to IVUS or angiography alone [32]. Efficacy of OCT-guided PCI to improve event-free survival after DES will be evaluated in the upcoming ILUMIEN IV trial.

Fractional flow reserve (FFR) is a guideline-recommended technique for guiding the use of PCI based on findings from multiple trials such as DEFER, FAME, and FAME II [33‐35]. It was thus surprising that the FUTURE trial [36] (Does FFR-guided treatment strategy in patients with multivessel CAD improve prognosis compared to traditional treatment), which planned to enroll 1728 patients, was halted prematurely after interim analysis suggested a higher 12-month mortality in the FFR group (4% vs 2%; p = 0.02). Subsequent follow-up of 797 reaching 12-month follow-up showed a small numerical excess in all-cause mortality, but this was no longer significant (p = 0.07) and thought likely to be a spurious finding.

With ever-older patients coming for PCI, strategies to adequately prepare heavily calcified lesions are increasingly needed. The novel technique of lithoplasty (high energy ultrasound waves) was evaluated in 60 patients undergoing PCI in the DISRUPT CAD (Shockwave Coronary Rx Lithoplasty^® Study trial). No angiographic complications were reported and OCT confirmed circumferential calcium fracture and luminal gain [37]. Larger studies with longer follow-up are required to assess the impact on clinical outcomes.

Transcatheter aortic valve implantation (TAVI) is now an accepted treatment method for patients with severe aortic stenosis who are at high risk for surgical aortic valve replacement (SAVR) based on data from the Placement of Aortic Transcatheter Valves (PARTNER) study [38]. The PARTNER 2 trial aimed to evaluate TAVI in the setting of severe aortic stenosis and intermediate risk. In total, 2032 patients, of whom 81.3% had an STS [Society of Thoracic Surgeons] score between 4–8, were randomized (1:1 ratio) to TAVI (Edwards Lifesciences Sapien XT) or SAVR [39]. TAVI was non-inferior to SAVR with regard to the primary endpoint of death or disabling stroke at 2 years (19.3% vs 21.1%; p = 0.001) and the transfemoral access TAVI cohort had lower rate of death or disabling stroke than SAVR (hazard ratio 0.79; 95% CI 0.62–1.00; p = 0.05).

While PARTNER 2 supports consideration of TAVI as an alternative to SAVR for severe aortic stenosis and intermediate risk patients, careful patient selection is still required as highlighted by data from the German Aortic Valve Registry [40] where, among 5997 intermediate risk patients (logistic EuroSCORE I of 10–20%) undergoing isolated valve treatment, higher mortality rates were reported for TAVI vs SAVR, in hospital (3.8% vs 2.6%; p = 0.02), at 30 days (4.6% vs 3.2%; p = 0.01) and at 1 year 16.6% vs 8.9%; p = 0.001). Confounding factors including frailty and other co-morbidities may not have been fully accounted for, but intermediate to lower risk patient groups require further study.

As TAVI implant numbers increase, growing concern surrounds the incidence of transcatheter heart valve thrombosis. At ESC 2016, data were presented from a cohort of 405 intermediate risk patients (mean STS score 5.3) undergoing TAVI with Edwards Sapien XT or Sapien 3 who were subsequently evaluated by cardiac CT 1–3 months later for evidence of hypoattenuated leaflet thickening suggesting valve thrombosis [41]. Overall, valve thrombosis was observed in 28 (7%) patients, of whom five had clinically obstructive symptoms but 23 were subclinical. Valve thrombosis was more common in those not receiving warfarin (10.7% vs 1.8%; risk ratio 6.09; 95% CI 1.86–19.84) and with larger valves. Treatment with warfarin effectively resolved valve thrombosis and normalized function in 85% of patients. Data regarding optimal antithrombotic therapy post TAVI is limited, but ongoing randomized trials such as the Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy to an Antiplatelet Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes (GALILEO: NCT02556203) study may guide preferred antithrombotic strategy.

Embolism of atherothrombotic debris is common following TAVI. The SENTINEL trial tested whether transcatheter embolic protection (TCEP) during TAVI would decrease periprocedural neurological events and cerebral infarction. In SENTINEL, 363 high risk patients undergoing TAVI were randomized (2:1) to receive TCEP or routine (non-TCEP) care. Evidence captured embolic debris in 99% of patients receiving TCEP. There was a small, non-significant increase in vascular complications with TCEP placement (8.6% vs 5.9%). At 30 days, numerically lower MACCE (7.3% vs 9.9%) and numerically lower strokes (5.6% vs 9.1%) were reported with TCEP, although these did not reach statistical significance [42]. In a subgroup undergoing brain MRI within 1 week, new lesion volume was numerically smaller with TCEP (102.8 vs 178.0 mm³; p = 0.33) but this did not reach statistical significance. Results are thus encouraging but further studies are needed. The degree of confirmed embolism detected also highlights the importance of avoiding overly aggressive device manipulation within the aortic valvar complex.

Extended follow-up from PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF) and PREVAIL (Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation vs long-term warfarin therapy) were presented at TCT 2016 as part of the CAP (Continued Access to PROTECT AF) and CAP2 (Continued Access to PREVAIL) registries [43] (Fig. 5). A total of 732 device patients were followed up for 5 and 3 years, respectively. Baseline predicted stroke risk was 3.6% based on a median CHA2DS2-VASc score of 3.4. Procedural complications included major bleeding (2.3%), stroke (1.0%), and device embolization (0.5%). Risk ratios for ischemic stroke, hemorrhagic stroke, and major bleeding post-procedure were 1.35, 0.16, and 0.62, respectively. The extended CAP follow-up suggested that Watchman is associated with a similar stroke risk reduction to that which would be expected with oral anticoagulants.

The significance and treatment of patent foramen ovale (PFO) in patients with cryptogenic stroke has been controversial. RESPECT (Closure of Patent Foramen Ovale vs Medical Therapy after Cryptogenic Stroke) 10-year outcome data followed 980 patients with cryptogenic stroke, randomized 1:1 to AMPLATZER PFO Occluder device vs medical management between 2003 and 2011 [44]. PFO closure using the AMPLATZER device was associated with a 45% risk reduction (p = 0.046) in recurrent ischemic stroke. There were no incidents of device embolization or thrombosis, and major vascular complications were low (0.9%). PFO closure with the AMPLATZER device in appropriate patients thus appears to be associated with superior long-term outcomes compared with medical management alone.

The STAMPEDE (Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently) trial (NCT00432809) has previously reported short-term improvement in outcomes for overweight patients with poorly controlled diabetes randomized to bariatric surgery plus medical therapy (n = 100) or to medical therapy alone (n = 50), but long-term results were awaited with interest [45].

At 5 years, bariatric surgery was associated with greater weight reduction in body weight (−23%, −19%, and −5% in the gastric bypass, sleeve gastrectomy, and medical therapy groups, respectively), triglyceride level (−40%, −29%, and −8%), and a greater achievement of the primary endpoint of normoglycemia defined as HbA1C ≤6.0% (29%, 23%, and 5%). While such metabolic improvements would hopefully be associated with improved CV outcomes, STAMPEDE was not powered to assess this and larger studies of this promising technique are planned.

While older hypoglycemic treatments for diabetes have failed to show clear CV benefit, The sodium–glucose cotransporter 2 inhibitor empagliflozin did show reduction in CV death, but the mechanism was unclear given the absence of reduction in MI or stroke [25].

While it was hoped that GLP-1 receptor agonists would be beneficial, the previous Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial in patients with diabetes and a recent ACS failed to show CV benefit [46]. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial randomized 9340 patients with diabetes (HbA1c ≥7%) and high CV risk to liraglutide 1.8 mg once daily or placebo [47]. Liraglutide was associated with a significant reduction in the primary outcome of CV death, MI, or stroke (13.0% vs 14.9%, HR 0.87, 95% CI 0.78–0.97; p = 0.01), all-cause mortality (8.2% vs 9.6%; p = 0.02), CV death (4.7% vs 6.0%; p = 0.007), and MI (6.3% vs 7.3%; p = 0.046). No increase in heart failure was reported (unlike with some DPP-4 inhibitors). Subsequently, semaglutide, which has an extended half-life allowing once-weekly administration, was evaluated in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) which randomized 2735 patients (1:1:1:1) to either 0.5 mg or 1.0 mg of once-weekly subcutaneous administration of semaglutide or volume-matched placebo. Semaglutide was associated with a significant reduction in the primary outcome of CV death, MI, or stroke [6.6% vs 8.9%; hazard ratio 0.74; 95% CI 0.58–0.95; p = 0.02] and reduction in stroke (1.6% vs 2.7%; p = 0.04) [48]. There was only a trend to reduced non-fatal MI (2.9% vs 3.9%, p = 0.12) and no difference in CV death or all-cause mortality, although follow-up was relatively short at 2 years.

In summary, given their favorable CV benefits, empaglifozin, liraglutide, or possibly semaglutide should now be considered as second-line therapy in diabetic patients at high CV risk.

Previous trials have demonstrated that high dose statins may be associated with reduction in coronary atherosclerosis volume as quantified by IVUS. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors when added to statin therapy are associated with marked further reductions in LDL-C, but it was not known if this would be associated with further reduction in atherosclerosis volume. The GLAGOV trial (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) randomized 968 patients (baseline mean LDL-C level 2.4 mmol/l) with angiographically moderate coronary atheroma to monthly evolocumab 420 mg or placebo for 76 weeks in addition to moderate–high intensity statins. Evolocumab reduced LDL-C to an average of 0.94 mmol/l. On repeat IVUS at 78 weeks, percentage atheroma volume (primary endpoint) was decreased by 0.95% with evolocumab vs an increase of 0.05% with placebo (between group difference 1.0%; p < 0.001). Overall, plaque regression occurred in significantly more evolocumab patients (64.3% vs 47.3%; p < 0.001) [49]. In an exploratory subgroup analysis of patients already achieving the current ESC treatment goal of LDL-C less than 1.8 mmol/l, those receiving evolocumab achieved a mean LDL-C of 0.6 mmol/l which was associated with an even greater regression of atheroma (−1.97% change in percentage atheroma volume and 81% of patients showing regression). Given these IVUS findings and post hoc clinical outcomes observed in phase 2 trials, results of the phase 3 outcome trial are eagerly awaited.

Patients with heterozygous familial hypercholesterolemia (HeFH) and LDL-C levels too high to be controlled by statin alone may currently be treated with serial lipoprotein apheresis which entails significant expense, patient inconvenience, and often lengthy travel to a regional lipid center. Given the marked LDL-C reduction possible with PCSK9 treatment, ODYSSEY-ESCAPE (NCT02326220) randomized HeFH patients undergoing lipoprotein apheresis in blinded fashion to alirocumab 150 mg twice monthly vs placebo. Apheresis was deferred if LDL-C was at least 30% lower than the baseline (pre-apheresis) value. Use of alirocumab significantly reduced requirement for apheresis with 63.4% of patients on alirocumab avoiding all and 92.7% avoiding at least half of the apheresis treatments [50]. This has significant implications for HeFH patients and may offer potential cost savings.

A further indication for PCSK9 inhibition may be use in patients with statin intolerance. GAUSS-3 (NCT01984424) randomized 218 patients prospectively confirmed during run in as having atorvastatin intolerance to evolocumab 420 mg once monthly or ezetimibe 10 mg daily. As expected, by 24 weeks evolocumab showed significantly greater reduction in LDL-C (−52.8% vs −16.7%; p < 0.001) but importantly there was no signal of excess myalgia with evolocumab; indeed the rate of discontinuation for muscle symptoms was numerically less (0.7% vs 6.8%) [51]. Thus, PCSK9 inhibitors offer a new treatment option in selected patients with statin intolerance.

A novel approach for reducing PCSK9 activity is to inhibit liver synthesis of PCSK9 by use of small interfering RNAs (siRNAs) which selectively silence the translation of PCSK9 messenger RNA (mRNA). Inclisiran, a chemically synthesized siRNA, has been shown to produced sustained hepatocyte-specific, PCSK9-specific RNA silencing in healthy volunteers up to 84 days after administration (Fig. 6).

Prespecified 90-day interim analysis (n = 497) from the phase II ORION 1 trial presented at AHA 2016 reported that a single dose of inclisiran 300 mg achieved a mean 51% LDL-C reduction at day 60 and 45% LDL-C reduction by day 90. A double 300 mg injection strategy, the first on day 1 and the second on day 90, achieved a mean LDL-C reduction of 57% at day 120 and 52% LDL-C reduction by day 180 [52]. These results support an attractive 4–6 monthly injection dosing schedule. Complete ORION 1 results are expected in 2017 and will help guide the phase 3 clinical outcome trial programme.

While interest mounts in methods to target the PCSK9 pathway, it continues to wane regarding the cholesteryl ester transfer protein (CETP) pathway. CETP inhibition is associated with favorable effects on HDL-C, LDL-C, lipoprotein(a), and cholesterol efflux, but previous studies have failed to demonstrate reduction in MACE. Evacetrapib, a potent CETP inhibitor but which lacks off-target aldosterone effect seen with torcetrapib, was tested in the large phase III ACCELERATE (NCT01687998) trial. A total of 12,072 patients at high vascular risk were randomized with evacetrapib achieving a 130% increase in HDL-C and 37% reduction in LDL-C vs placebo [53]. However, the trial was stopped early because of futility with no significant difference in clinical outcomes demonstrated.

The importance of a multi-risk factor approach to CV risk reduction is well recognized. HOPE 3 (NCT00468923) aimed to determine the CV benefit of antihypertensives, rosuvastatin, or their combination in an ethnically diverse population without previous CV disease recruited based on overall intermediate CV risk rather than requiring specific BP or LDL-C levels. In total, 12,705 patients with a mean BP of 138/82 mmHg and mean LDL-C of 3.2 mmHg were randomized in 2 × 2 factorial trial design into three arms. After 5.6 years follow-up, in the first arm, antihypertensive treatment (hydrochlorothiazide 12.5 mg, candesartan 16 mg) vs placebo which achieved a mean BP reduction of 6/3 mmHg showed no overall difference in the CV death, stroke, or MI (4.1% vs 4.4%), although in the highest BP tertile (systolic BP >143.5 mmHg), there was 27% reduction (HR 0.73; 95% CI 0.56–0.94). Symptomatic hypotension was 1.7 times more common with antihypertensive therapy (3.4% vs 2.0%; p < 0.001). In the second arm, rosuvastatin 10 mg vs placebo was associated with a 24% reduction in CV death, stroke, or MI (3.7% vs 4.8%, HR 0.76, 95% CI 0.64–0.91; p = 0.002). In the third arm rosuvastatin plus antihypertensive therapy vs placebo was associated with a 29% in CV death, stroke, or MI (3.6% vs 5.0%, HR 0.71, 95% CI 0.56–0.9; p = 0.005) [54]. In summary, primary prevention with statin therapy in this intermediate risk population was effective, whereas antihypertensive therapy was not of benefit in the absence of elevated BP but was associated with adverse events which thus calls into question the need to routinely include antihypertensives in a polypill approach.

Cardiac rehabilitation following a CV event is associated with improved outcomes but the optimum duration is unknown. In the OPTICARE trial (NCT01395095), following ACS and a standard 3 months of cardiac rehabilitation, 914 patients were randomized to no further therapy, an additional 9 months of group therapy or an additional 9 months of telephone support. Overall, the prolonged programmes were not associated with further improvement in CV risk markers. However, compliance with the prolonged programmes was suboptimal and when only those attending more than 75% of sessions were assessed, an additional 9 months of group therapy was associated with a 37% reduction in smoking (13.4% vs 21.3%; p < 0.001) and a 9% reduction in total cholesterol (3.9 vs 4.3 mmol/L; p < 0.001) [55]. This suggests that in motivated patients, a 1-year group rehabilitation programme may be of additional CV benefit. In contrast, additional telephone support was of unclear benefit.

ESC guidelines recommend opportunistic screening for AF in patients over 65 (level 1B) by means such as pulse assessment or rhythm strip analysis, although it is recognized that this may fail to detect many paroxysmal episodes of subclinical AF. Previous trials in patients with pacemakers or ICDs have shown that subclinical AF (atrial high rate episodes) is common and is associated with increased incidence of subsequent stroke but the prevalence in patients not requiring a device has been unknown. The ASSERT II trial (Prevalence of Sub-Clinical Atrial Fibrillation Using an Implantable Cardiac Monitor; NCT01694394) recruited 256 patients aged 65 years and over with at least one clinical risk factor (CHADS2VASC ≥2, obstructive sleep apnea, or BMI >30) and one echo or biochemical risk factor (left atrial diameter ≥4.4 cm, left volume ≥58 mL, or NT-ProBNP ≥290 pg/ml). All patients received an implantable loop monitor (Confirm DM2100; St Jude Medical) for between 9 and 18 months. The annualized incidence of subclinical AF of at least 5 min was common—observed in 34.4% of patients per year—and was almost twice as common in patients with left atrial volume greater than 73.5 mL (51.9% vs 27.4%; p = 0.015) but, of interest, it was not any more common in the fifth of patients with a prior history of stroke [77]. Thus, it remains unclear if all subclinical AF patients require anticoagulation, and further studies are investigating this key question including ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; NCT01938248) and NOAH (Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes; NCT02618577).

The use of non-vitamin K antagonist oral anticoagulants (NOAC) has revolutionized anticoagulation in atrial fibrillation. However, many concerns still exist over the place of these agents following major bleeding, PCI, and in planned cardioversion. Several trials presented in 2016 aimed to address these specific areas.

Despite landmark clinical trial data, the previous lack of specific NOAC reversal agents posed concern for some clinicians. Idarucizumab is now approved for reversal of dabigatran [25]. Andexanet, a factor Xa decoy protein, has previously been shown, among healthy volunteers, to reduce anti-Xa activity and to restore thrombin generation. ANNEXA-4 (Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors; NCT02329327) evaluated 67 patients who had acute major bleeding within 18 h after the administration of a factor Xa inhibitor (rivaroxaban, apixaban, or enoxaparin) [78]. All received a 30-min bolus followed by a 2-h infusion of adexanet. Dose was determined on timing of last administration of factor Xa inhibitor. After the bolus dose median anti-factor Xa activity decreased by 89–93% (with similar suppression maintained during the 2-h infusion). By 4 h after the infusion there was partial recovery of anti-factor Xa activity (30–39% reduction from baseline) but by 12 h, 79% of patients had achieved clinical hemostasis (Fig. 8).

Of note, thrombotic events occurred in 12 patients and 10 died (six due to cardiac cause) during 30-day follow-up. Overall, andexanet appears a useful option although given the short plasma half-lives of the anticoagulants studied, the relatively long median 4.8-h delay from presentation to the administration of andexanet, and the absence of a placebo arm, it cannot be determined how many patients would have achieved hemostatic efficacy without andexanet. Further refinements in the administration of andexanet could lead to more complete reversal of anti-factor Xa activity and improved clinical outcomes.

An ongoing important area of uncertainty relates to patients with AF undergoing PCI. In the absence of definitive trial data, current ESC revascularization guidelines for non-ST elevation MI [79] suggest different treatment strategy options: (class IIa) triple therapy (anticoagulant, aspirin plus clopidogrel) for 6 months in low-bleeding-risk patients or for 1 month in high-bleeding-risk patients and (class IIb) anticogulation plus clopidogrel only as an alternative to triple therapy in selected patients (based on WOEST study data).

PIONEER-AF (Patients with atrial fibrillation undergoing coronary stent placement; NCT01830543) is the first study to compare a NOAC with warfarin in this setting and randomized 2124 patients (Fig. 9) to (group 1, “WOEST-like”) rivaroxaban 15 mg once daily with a single P2Y12 inhibitor for 12 months; (group 2, “ATLAS ACS 2-like”) rivaroxaban 2.5 mg twice daily with DAPT for 1, 6, or 12 months at the operators discretion then, as needed, rivaroxaban 15 mg once daily plus aspirin until 12 months; or (group 3, “triple therapy”) warfarin with DAPT for 1, 6, or 12 months at the operator’s discretion then, as needed, warfarin plus aspirin until 12 months [80]. DAPT duration was 1 month in 16%, 6 months in 35%, and 12 months in 49%. Clopidogrel was the P2Y12 inhibitor used in 95% of cases. Clinically relevant bleeding was reduced in patients receiving rivaroxaban vs warfarin (group 1, 16.8% and group 2, 18% vs group 3, 26.7%; p < 0.001 for both). TIMI major bleeding was numerically less but not significant (2.1% vs 1.9% vs 3.3%). Stent thrombosis rates were similar (0.8% vs 0.9% vs 0.7%) and were equivalent between groups. Although the composite of CV death, MI, or stroke was similar between groups (6.5%, 5.6% vs 6.0%) the study was not powered to test efficacy and wide confidence limits could not exclude an excess of events with rivaroxaban. Reduced all-cause re-hospitalization with rivaroxaban was described in post hoc analysis.

It would be helpful to have further trials powered for efficacy and to include a warfarin “WOEST arm” (warfarin plus clopidogrel for 12 months since this was associated with reduced MACE in WOEST). However, given the reduction in bleeding and convenience of a simple double therapy for 12 months rather than triple therapy with stepdown to double, rivaroxaban 15 mg once a day plus single antiplatelet therapy may become the approach of choice once approved.

Following a major bleeding event clinicians are faced with the dilemma of whether to recommence anticoagulants. A recent US observational study has suggested improved outcomes in those who are restarted on anticoagulants following a bleeding event. A large Danish registry study identified 2662 patients with AF who had suffered a hemorrhagic stroke or traumatic intracranial bleed while on anticoagulants [81]. In those that restarted oral anticoagulants there was an overall reduction in all-cause mortality at a mean of 2.1 years follow-up. In those with hemorrhagic stroke there was a non-significant trend towards increased risk of recurrent intracranial hemorrhage but no signal was seen for those with prior traumatic intracranial bleed. Findings thus support reinitiation of anticoagulants following intracranial hemorrhage but further work is required to determine optimum timing of reinitiation and patient risk stratification.

The use of NOACs in place of warfarin to support cardioversion has, to date, been based on retrospective analysis of the general AF trials and a smaller prospective study with rivaroxaban. ENSURE-AF (Edoxaban vs enoxaparin–warfarin in patients undergoing cardioversion of atrial fibrillation; NCT02072434), the largest prospective trial to compare a NOAC with optimized warfarinization (including bridging enoxaparin until INR was therapeutic for more than 2 days) randomized 2199 patients to edoxaban vs warfarin. The warfarin group received optimized treatment. There was a non-significant numerical reduction in the composite of CV death MI, stroke, embolism, or major bleeding (0.7% vs 1.4%; OR 0.50, 95% CI 0.19–1.25) although ENSURE AF was not powered to fully test these outcomes [82]. Edoxaban appeared similarly useful whether cardioversion was undertaken after a conventional 3-week course of anticoagulation or transesphageal echocardiogram-guided cardioversion within a few days. Overall, this study adds to previous trial data suggesting that a NOACs-supported approach appears an effective alternative to conventional VKA-based anticoagulation for pericardioversion use.

Pulmonary vein isolation using radiofrequency (RF) ablation has become an established treatment for AF refractory to pharmacological management, although the previous complexity and duration of the procedure have limited its availability. An alternative method using cryogenic energy delivered via balloon (cryoballoon) offers a significantly reduced procedural time. The FIRE AND ICE trial (NCT01490814) randomized 762 patients to cryoballoon vs RF ablation. Cryotherapy was associated with shorter procedural time (124 vs 14 min; p < 0.001) [83]. At a mean of 1.5 years, there was no difference in the primary endpoint of recurrence of atrial arrhythmia, use of anti-arrhythmic agent, or repeat procedure (34.6% with cryoballoon cohort vs 35.9% with RF, CI 0.76–1.22; p < 0.001 for non-inferiority). Phrenic nerve injury was seen in 2.7% of cryoballoon cases, although all but one resolved by 12 months. This trial further supports the use of cryoballoon ablation as an option for AF ablation. The second-generation cryoballoon has also shown improvement in long-term pulmonary vein isolation likely attributable to the extensive wide-area circumferential ablation that is achieved.