Pascal Meier1,2, Olaf Franzen3, Alexandra J Lansky2
1 Yale – UCL Cardiovascular Research Program, The Heart Hospital, University College London Hospitals UCLH, London, UK
2 Division of Cardiology, Yale Medical School, New Haven, Connecticut, USA
3 Division of Cardiology, Rigshopitalet University Hospital Copenhagen, Copenhagen, Denmark
* Meier P, Franzen O, Lansky AJ. Heart Published Online First: Heart 2013 Sep;99(18):1309–16. doi:10.1136/ heartjnl-2013-304430.
Dr Pascal Meier, Yale – UCL Cardiovascular Research Program, The Heart Hospital, University College London Hospitals, UCLH16-18 Westmoreland Street, London W1G 8PH, UK; E-mail: firstname.lastname@example.org
Received on 10 June 2013. Revised on 27 June 2013. Accepted on 30 June 2013.
Abstract: Recent innovations in interventional cardiology have dramatically expanded the therapeutic options for patients with cardiac conditions. Interventional cardiology is no longer limited to the treatment of coronary artery disease but allows also treatment of valvular disease, stroke prevention, hypertension, etc. One of the most important new treatment options is the percutaneous treatment for aortic valve stenosis (transcatheter aortic valve implantation), since aortic valve disease is a rather common problem in elderly patients, with many of them at high risk for surgery. Similarly, mitral regurgitation is often associated with comorbidities which make surgery high risk. The MitraClip is a promising percutaneous alternative to surgical valve repair or replacement. Other procedures discussed in this review are the percutaneous left atrial appendage closure as a non-pharmacologic therapy to prevent strokes, and renal denervation for resistant hypertension. This review explains the basic principles of these procedures, the most important clinical evidence, and also provides additional recent clinical data on each of these them.
After Andreas Gruentzig’s pioneering balloon angioplasty, percutaneous coronary interventions became the mainstay of cardiology for the ensuing decades1; that is until very recently when cardiology has adopted innovations which can be regarded as revolutionary as Gruentzig’s angioplasty. Foremost in the development of percutaneous treatment options for aortic valve stenosis, transcatheter aortic valve implantation (TAVI) has improved the treatment options for elderly patients with aortic valve stenosis. Other important developments are the percutaneous treatment options for mitral regurgitation (MR) (MitraClip), non-pharmacologic therapy to prevent cerebral embolization in patients with atrial ﬁbrillation (AF) such as left atrial appendage (LAA) closure and closure of the patent foramen oval, and renal denervation to treat resistant hypertension.
LEFT ATRIAL APPENDAGE CLOSURE
AF is very prevalent and the main cause of stroke. The lifetime risk of developing AF is approximately 1 in 42. It is likely that the true prevalence is underestimated, because it can be difﬁcult to detect paroxysmal AF. Patients with paroxysmal AF probably have a risk of stroke that is similar to patients with persistent AF3.
Oral anticoagulation has always been the ﬁrst line treatment to prevent stroke, but it comes with considerable risks, The narrow therapeutic window of warfarin forces a delicate balance between lack of efﬁcacy and a signiﬁcantly elevated risk of bleeding, therefore requiring frequent blood tests. Additionally, numerous food and drug interactions exist which have a major impact on the patient’s daily life. Up to 40% of patients with AF have contraindications to anticoagulation therapy. Even in trial settings, a relevant proportion of patients are either sub- or supratherapeutic on warfarin. In a study of 41 900 patients with chronic AF, only 70% of patients treated with warfarin remained on this therapy at 1 year, further highlighting difﬁculties with anticoagulation.
Among patients with non-valvular AF, the vast majority of thrombi evolve from the LAA. The ﬁbrillating LAA is a cul-de-sac that creates a milieu for blood stasis and thrombus formation. Therefore, one could expect that exclusion of the LAA from the circulation could reduce the risk for stroke. Several methods have been developed – surgical ligation or amputation and percutaneous catheter based occlusion with speciﬁc occlude devices (Figure 1).
Surgical ligation or amputation has been used for many years even though there is very little evidence regarding its effectiveness5. Of course, it is only performed as a ‘bystander’ operation in the case of, for example, valve surgery, not as a stand alone procedure6.
Percutaneous methods have been developed since 2002. Preliminary studies of two systems speciﬁc- ally designed for this purpose (Percutaneous LAA Transcatheter Occlusion (PLAATO) and Watchman systems) have been completed7. These devices are deployed via a venous access and transseptal crossing into the left atrium (LA). These devices are CE (European Conformity) marked in Europe but are not approved by the US Food and Drug Administration (FDA) for clinical use yet.
In addition to these two systems, the Amplatzer cardiac plug and the Lariat (snare device) system are also available.
The PLAATO system was a device that was placed in the LAA via a transseptal catheter. It had a self-expanding nitinol frame that was covered by a fabric that was impermeable to blood, thus sealing the LAA and preventing thrombus formation or dislodgement. However, there were adverse effects during follow-up – for example, pericardial effusion in eight patients, two strokes, two transient ischaemic attacks, and three non-procedural deaths8. The manufacturer has discontinued development of the PLAATO device.
The Watchman device also involves an expandable device deployed in the LAA via a transseptal catheter. The implanted device has a self-expanding nitinol frame to secure it in the LAA. Unlike the PLAATO device, the fabric of the Watchman device is permeable to blood9. For this reason, patients require conventional thromboembolic prophylaxis with warfarin until the device is endothelialized (eg, at least 45 days post-implant), at which time transoesophageal echocardiography is performed to ensure endothelialization. In addition, all patients are treated with both aspirin (81-325 mg) and clopidogrel (75 mg) daily for 6 months.
The Watchman device was evaluated in the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF) trial in which over 700 patients with non-valvular AF were randomly assigned in a 2:1 ratio to either the device (with the above antithrombotic regimen) or to long term warfarin (international normalized ratio 2.0 to 3.0)10. It had a non-inferiority design. Inclusion criteria allowed for patients with paroxysmal, persistent, or permanent AF and all patients had a CHADS2 score ≥1.
The trial conﬁrmed non-inferiority of Watchman atrial appendage occlusion compared to warfarin therapy regarding the primary end point, a composite of stroke, systemic embolism, and cardiovascular death with a risk ratio of 0.62 (95% CI 0.35 to 1.25)11. However, the primary safety end point (composite of major bleeding, pericardial effusion, procedure related stroke, and device embolization) was increased in the device group (7.4 vs 4.4 events per 100 patient-years, respectively). Most of the events in the device group occurred early. Of these, about 50% were pericardial effusions requiring drainage.
Two later registries showed improving safety of this device, probably due to a learning curve effect. The rate of complications within 7 days were 3.7% as compared to 7.7% in the initial randomized trial11,12.
AMPLATZER SEPTAL OCCLUDER AND AMPLATZER CARDIAC PLUG
The Amplatzer septal occluder uses a simpler technique than the PLAATO technique. Instead of general anesthesia as used in the PLAATO procedure, it is often implanted under local anesthesia. A case series involving 16 patients demonstrated the use of the Amplatzer septal occluder to close LAA under local anaesthesia without echocardiographic guidance13. The Amplatzer cardiac plug is another device designed speciﬁcally for closure of the LAA and is undergoing clinical trials14. This device is nitinol based and consists of a left atrial disk and a distal plug connected to the left atrial disk by a short waist. The distal plug contains six pairs of barbs designed to increase stability within the appendage. This device is shorter than the Watchman device and may be more advantageous in individuals with the variable morphology of the appendage. Animal data have been published demonstrating uncomplicated device delivery with complete occlusion of the appendage at 30-day and 90-day follow-ups14,15.
The future role of this procedure will also depend on other alternatives to warfarin therapy, such as the novel anticoagulants. So far, there is no strong evidence suggesting they are superior to warfarin, apart from rivaroxaban which showed a lower bleeding risk, but they are a promising alternative to warfarin and much easier to use16.
The 2012 focused update of the European Society of Cardiology (ESC) guidelines for the management of AF makes a weak recommendation for the use of interventional, percutaneous LAA closure in patients with a high stroke risk and contra- indications for long term anticoagulation17. In conclusion, percutaneous LAA closure seems as effective as warfarin according to one randomized trial, but comes with periprocedural complications (such as pericardial effusion).
Left atrial appendage closure:
- Percutaneous LAA closure is a promising alternative to warfarin therapy in patients with AF who have a high stroke risk.
- Data are scarce and the procedure should be limited to patients who have clear contraindications for warfarin.
- Novel anticoagulants (eg. rivaroxaban) represent another alternative for patients with a contraindication for warfarin.
MITRAL VALVE INTERVENTIONS
The prevalence of moderate or severe MR is over 10% in those older than 75 years and the natural course is often fatal18. However, patients with chronic severe MR often have other comorbidities that increase their risk for cardiac surgery. There is an urgent need for a less invasive percutaneous approach. Several approaches have been tested. Currently, the most promising one is the MitraClip system (Abbott Laboratories, Abbott Park, Illinois, USA). It is based on the surgical Alﬁeri stitch technique, an edge-to-edge repair (Figure 2)19.
The MitraClip system consists of a catheter to guide the path of the clip delivery and a clip delivery system which includes the detachable clip with a Dacron cover to enable tissue ingrowth. The clip delivery system has a control mechanism to open and close the two arms of the clip. Tissue of the mitral leaﬂet is held between the arms and each side of the U-shaped gripper. Then, the clip is closed and locked so that the two leaﬂets stay approximated for repair.
Usually under general anesthesia, the guide catheter is inserted through the femoral vein to reach the left atrium through a transseptal approach. Using this path, the MitraClip is delivered and deployed. The clip delivery system aligns the MitraClip with the line of coaptation, tissues of the mitral valve leaﬂet are grasped, and the clip is partially closed to about 60°. Ideal length for cooptation is at least 2 mm. Transoesophageal echocardiography (TOE) is used to guide the deployment of the clip and later to evaluate the reduction in MR. Periprocedural imaging is key for this procedure, as it should be the case for surgical mitral valve repair; the mitral valve is a relatively complex structure20. If there is adequate leaﬂet insertion at 60° of clip closure, the clip is further closed to appose the leaﬂets and induce cooptation to reduce MR maximally in patients with either degenerative or functional MR. In order to avoid a stenosis following placement of the MitraClip, the baseline mitral valve area should have been >4 cm2.
The initial human clinical experience with MitraClip was studied in the EVEREST (Endovascular Valve Edge-to-Edge Repair Study) phase I study21. The study included 27 patients. Fourteen of the patients had MR reduced to ≤2+ at 6 months. The study showed promise for MR patients at high risk for conventional surgical procedures.
The pivotal EVEREST II trial randomized 279 patients with chronic moderately severe or severe MR (grade 3+ or 4+) to undergo either percutaneous MitraClip or mitral valve surgery in a 2:1 ratio22. Although before hospital discharge percutaneous therapy was less effective at reducing MR, the rates of MR reduction at 12 and 24 months were similar in both the groups. However, percutaneous therapy was found to be safer with a reduced rate of major adverse events at 30 days. The study showed sustained clinical improvement, as assessed by quality of life, heart failure status, and left ventricular function.
The EVEREST II study was not speciﬁcally focused on very high risk patients. The mean age was 66 years, mean ejection fraction was 60%, and major comorbidities were rare. In the EVEREST II High Risk Study (HRS), however, patients had severe MR (3–4+), a mean age of 77 years, and an estimated surgical mortality rate of ≥12%23. More than 50% of these patients had undergone previous cardiac surgery. They were compared retrospectively with a group of patients who were screened con-currently but not enrolled into the EVEREST II study. These patients had been treated by standard medical therapy.
The 30-day procedure related mortality rate was similar in both the groups (7.7% in the HRS vs 8.3% in the comparator group). The 12-month survival was higher in the HRS group (76% vs 55%). In surviving patients the baseline and 12-month data were compared. MR grade had reduced to ≤2+ in 78% patients. There was improvement in left ventricular end-diastolic volume (172-140 mL), end-systolic volume (82-73 mL), New York Heart Association functional class (III/IV at baseline in 89% to class I/II in 74%; p <0.0001), quality of life and mental component score at 12 months.
Feldman et al24 reported clinical results of use of the clip in a cohort of the ﬁrst 107 patients followed for as long as 3 years. These were 55 patients treated in the EVEREST phase I feasibility trial, and 52 roll-in patients treated in the EVEREST II pivotal trial representing the pre-randomization start-up experience. Out of the successfully treated patients, 66% achieved the primary end point of freedom from death, mitral valve surgery, or MR >2+ at 12 months. There was sustained freedom from death, surgery or recurrent MR in most patients even at 3 years.
The MitraClip device has received a CE approval and has already been used in thousands of patients worldwide25,26. Until approval is obtained from the FDA, the clip is available only through the REALISM continued access registry in the USA. Patients enrolled into this ‘real-world’ registry are assigned to either the high risk arm or the non-high risk arm. They are followed up at 30 days, 6 months and 12 months.
Interim results of the EVEREST II REALISM study were presented at the Society for Cardiovascular Angiography and Interventions (SCAI) 2011 scientiﬁc sessions27-29. On average, the age of patients in the registry was over 70 years. The MitraClip procedure was safe with a 30-day mortality of 3.8%28. At 1 year, 83% of patients in the high risk group had only mild to moderate MR (1+ or 2+). Before the procedure, the quality of life scores were worse for functional MR than for degenerative MR29, but there was also greater improvement after the procedure.
An analysis of the ﬁrst 100 patients in the MitraSwiss register from Switzerland showed that congestive heart failure before clip implantation and previous coronary artery bypass grafting (CABG) were predictors of poor outcome with the MitraClip procedure26. A reduction of MR to ≤2+ during the procedure and a low grade MR at discharge predicted better mid-term survival. Gaemperli et al30 documented an improvement in the haemodynamic proﬁle immediately after the procedure. This acute haemodynamic improvement was associated with favorable mid-term outcome.
In conclusion, the MitraClip implantation is inferior to surgical mitral repair for reducing MR grade, but it is probably safer in higher risk patients. Even though the reduction in MR is less than with surgery, the subjective symptom improvement is comparable. The most suitable patients are those at high risk for surgery and particularly those with functional MR. The optimal time point for the procedure is not clear, but for patients undergoing surgery the data indicate that sooner is probably better31. This makes sense, as surgery has become safer and has changed the risk–beneﬁt considerations. Since the percutaneous approach has further reduced the periprocedural risk, the same consideration should apply here as well.
Mitral valve interventions:
- Data for the MitraClip system procedure are very limited and derive mainly from the EVEREST II trial.
- Even though the EVEREST trial did not enroll very high risk patients, the procedure should be limited to those at high surgical risk because of the limited effect.
AORTIC VALVE INTERVENTIONS
Aortic valve stenosis (AS) is a very common disease, with increasing prevalence at older age32,33. In properly selected patients, aortic valve replacement (AVR) substantially improves symptoms and increases life expectancy. However, for patients with major comorbidities, as is often the case in this elderly patient group, AVR surgery may not be appropriate because of the risks involved. A less invasive means is percutaneous aortic valvuloplasty, but this has a limited and usually only a temporary effect. Transcatheter aortic valve replacement (TAVR or TAVI) provides an alternative for treating AS in patients at high surgical risk. It is also a preferred option in patients who may have technical issues with surgery – for example, porcelain aorta or prior mediastinal radiation, or surgery with dense adhesions, or prior sternal infection with complex reconstruction, or a patent left internal mammary graft.
The most recent 2012 European guidelines state that TAVR is recommended in patients with severe symptomatic AS who are, according to the local ‘heart team’ (multidisciplinary team), considered unsuitable for conventional surgery because of severe comorbidities. Among high risk patients who are potential candidates for surgery, the decision should be individualized and discussed in a ‘heart team’. Risk scores can be helpful for the clinical decision making. The logistic EuroSCORE ≥20% is very established and often used in this setting as well; a score ≥20% has been proposed to deﬁne high risk. However, it generally overestimates operative mortality. Factors such as pulmonary hypertension or right ventricular dysfunction are not accounted for. The newer EuroScore II is probably more useful; alternatively, the Society of Thoracic Surgeons (STS) score can be used with a score ≥10% indicating high risk (a threshold of ≥8% was used in the PARTNER A trial). We have to be aware that no ‘perfect’ TAVI risk score has been established yet; they have been developed for patients undergoing cardiac surgery, pre- dominantly CABG. These scores do not consider factors which are important when debating TAVR versus surgical AVR, such as frailty, porcelain aorta, history of chest radiation or patent coronary bypass grafts. Therefore, the ﬁnal decision should be based on a comprehensive clinical judgment. Importantly, TAVI should currently not be performed in patients at intermediate surgical risk until more data for this group of patients are available, for example, from the ongoing SURTAVI (Surgery and Transcatheter Aortic Valve Implantation) trial (NCT01586910)34.
The 2012 American College of Cardiology (ACC) guidelines are very similar and equally endorse a multidisciplinary team decision for patients at high risk for surgery, deﬁning ‘too high risk for surgery’ as an estimated ≥50% risk of death or irreversible morbidity at 30 days35. Even though these guidelines are very recent, with increasing experience the indication for TAVR is rapidly expanding in some countries. In selected centers in Germany, TAVR accounts for over one-third of all AVR procedures. TAVR is a cost effective treatment for those who are not eligible for surgical AVR36. In the USA, the introduction of TAVR has been somewhat slower, mainly due to regulatory reasons35,37. Interestingly, in most centers, the introduction of TAVI has been associated with increase in conventional surgical AVR activity also38,39. Currently, two valves are in widespread use and have FDA approval – the balloon expanding Edwards Sapien transcatheter valve (THV) (Edwards Lifesciences, Irvine, California, USA) and the self-expanding CoreValve (Medtronic Inc, Minneapolis, Minnesota, USA).
The landmark trials for TAVR, the PARTNER (Placement of Aortic Transcatheter Valve) trials, have been performed with the Edwards Sapien valve. The subsequent Sapien Aortic Bioprosthesis European Outcome (SOURCE) Registry assessed results of the use of the Edwards Sapien valve in consecutive patients in Europe, with procedural success rates as high as 93.8% and a low incidence of procedure related complications40. Incidence of stroke was similar (2.5%) with both the transfemoral and the transapical approaches. The 30-day mortality was lower (6.3% vs 10.3%) and 1-year survival was higher (81.1% vs 72.1%) in patients with the transfemoral approach40,41. However, there was a much higher rate of vascular complications with transfemoral TAVR (22.9% vs 4.7%), probably because of the larger diameter of the delivery sheath.
Most TAVR teams prefer the transfemoral approach as it avoids surgical manipulation of the chest and reduces post-operative pain42. It is also the least invasive method43. However, thoracic epidural analgesia provided during transapical TAVR can signiﬁcantly reduce pain and periprocedural respiratory complications44.
The Edwards Sapien XT valve has a cobalt chromium frame with struts that are thinner and have a more open structure45. A trial on 120 patients showed that it had the same short term performance as the earlier SAPIEN valve but was associated with threefold lower risk of major vascular complications46.
The PARTNER valve trial was the world’s ﬁrst prospective randomized controlled trial for TAVR. It was designed with two arms:
- PARTNER A randomized 699 high surgical risk patients to either TAVR or surgical AVR
- PARTNER B randomized 358 inoperable patients to either TAVR or standard medical care.
The 30-day mortality was higher in TAVR patients than in those administered standard medical care (5% vs 2.8%, p=0.41) but was less for TAVR than in those undergoing open surgical AVR (3.4% vs 6.5%, p=0.07)47.
In the PARTNER A cohort, those who underwent TAVR had a higher incidence of major strokes (3.8% vs 2.1% at 30 days; 5.1% vs 2.4% at 1 year) and major vascular complications (11.0% vs 3.2% at 30 days; 11.3% vs 3.5% at 1 year). Those treated with surgical AVR had a higher incidence of major bleeding (19.5% vs 9.3% at 30 days; 25.7% vs 14.7% at 1 year) and new AF (16.0% vs 8.6% at 30 days; 17.1% vs 12.1% at 1 year).
Both surgical AVR and TAVR resulted in a decrease in aortic valve gradients and an increase in effective oriﬁce area (EOA) (p<0.0001) which remained stable over 2 years. TAVR was associated with higher indexed EOA, lower prosthesis–patient mismatch, and more aortic regurgitation (AR)48.
Though right ventricular function is reduced following surgical AVR, there is no such effect with TAVR49,50.
A recent study has shown that there is transient systolic and diastolic dysfunction within the ﬁrst 24 h of a successful TAVR51. This is associated with an increase in serum markers of myocardial injury and dysfunction suggesting that the post-procedural dysfunction is due to myocardial stunning and periprocedural injury to the myocardium.
Post-procedure paravalvular AR is more common after TAVR than after surgery52,53. We have learned from the PARTNER trials data, conﬁrmed by subsequent studies, that there is an association of post-TAVR paravalvular leak and increased mortality. Based on the German TAVR registry, the occurrence of signiﬁcant angiographically assessed AR immediately after TAVR was 17.2%. This population consisted of 84% Medtronic CoreValve systems and 16% Edwards Sapien valves. The risk for in-hospital mortality was increased around 2.5-fold in patients with signiﬁcant AR52. However, whether AR is a cause for mortality or just a marker for higher risk patients (severe calciﬁcation, tighter valves) is unclear. In this study, AR was an independent predictor of mortality in an adjusted analysis, but of course such adjustments are rarely able to eliminate con- founding entirely.
The survival in both the PARTNER A and PARTNER B trials was remarkably good. But stroke and perivalvular leakage associated with the Sapien valve required further evolution of the device.
Two large studies are being conducted with the Sapien XT device: the PARTNER II study and the ARTE (Aspirin Versus Aspirin and Clopidogrel Following Transcatheter Aortic Valve Implantation) trial. The later study is comparing the efﬁcacy of aspirin versus a combination of aspirin and clopidogrel following TAVR in preventing major ischaemic events45.
The PARTNER II study has recently started45. It consists of two arms: cohorts A and B. Cohort A will have 2000 patients with an STS risk score of ≥4. They will be randomized on a 1:1 basis to TAVR with the Edwards Sapien XT valve or to surgical AVR. There will be substratiﬁcation based on coronary artery disease (CAD). Patients with CAD will be randomized on a 1:1 basis to TAVR plus percutaneous coronary intervention and to surgical AVR plus CABG. A detailed pre- and post-procedural logical assessment will be done on all patients. Data for a frailty substudy will also be collected. Cohort B will have 500 inoperable patients who will be randomised on a 1:1 basis to TAVR with the Edwards Sapien THV and Edwards Sapien XT devices. The safety and efﬁcacy of the two devices will be compared. The study is expected to ﬁnish in 2018.
Edwards Lifesciences (USA) has developed two additional valves: the Centera and the Sapien III valves. Both these devices have recently entered ﬁrst-in-man studies.
Other than the Sapien device, the only other FDA approved device is the CoreValve (Medtronic Inc, Minneapolis, Minnesota, USA). It has porcine pericardial leaﬂets mounted on a self-expanding nitinol frame. It does not allow antegrade implantation, unlike the Sapien valve which can be implanted both antegrade as well as retrograde54. However, the advantage is that it uses a lower proﬁle delivery system of 18 French.
In the Medtronic CoreValve multicentre expanded evaluation registry, the initial procedural success was high (97%) and the procedural mortality was low (1.5%)55. The 30-day all cause mortality (including procedural) was also low (8%). These beneﬁts were sustained over time up to 1 year56. Ussia et al reported sustained clinical and functional cardiovascular beneﬁts over 3 years too. A recent presentation of the results of the ADVANCE CoreValve registry revealed an all cause mortality rate of 12.8% and a cardiac mortality rate of 8.4% at 6 months. Stroke rates were low (2.9% at 30 days) while the pacemaker implantation rate was 26.3%45.
This rather high rate of pacemaker implantation is often regarded as a limitation for the CoreValve system, when comparing it with the rates for the Edwards Sapien system and with the rate after surgical AVR. After surgical AVR, a recent large cohort study in 780 patients showed a need for a pacemaker implantation post-procedure of 3.2%57. However, the need for pacemaker for the self-expandable CoreValve system has decreased over time with technical iterations and operator’s experience. The valves are now implanted in a higher position, which has signiﬁcantly reduced electrical disturbances.
MRI tests have shown multiple small cerebral infarcts (in 77% cases) following TAVR. Most of the lesions were silent. Clinical stroke was associated with higher infarct number and volume58. The SIMPLIFy TAVI study (Transcatheter Aortic Valve Implantation Without Predilation) is investigating whether the avoidance of balloon valvuloplasty for predilation of the native aortic valve reduces the stroke risk during TAVI.
The CoreValve Advance II prospective registry is expected to deﬁne ways to reduce the need for permanent pacemaker implantation.
TAVR has also been tried successfully in several ‘off label’ indications such as in patients with bicuspid valves, severe MR, reduced left ventricular ejection fraction, and low gradient, low output AS59.
Other valves are currently under evolution. These include the Sadra Lotus valve (Medtronic Inc, Minneapolis, Minnesota, USA), Direct Flow Medical (DFM) valve (Direct Flow Medical Inc, Santa Rosa, California, USA), Symetis Acurate valve (Symetis SA, Ecublens, Switzerland), JenaValve (JenaValve, Munich, Germany), and the Engager valve.
EMBOLIC PROTECTION DEVICES
Cerebrovascular adverse events have been reported as complications of TAVI. Also, MRI studies have detected subclinical post-procedural embolic lesions following TAVR in over 90% of patients60. To address this issue, speciﬁc embolic protection devices are being developed. The Claret CE Pro system (Claret Medical, Inc, Santa Rosa, California, USA) has two ﬁlters to capture any debris that moves in the brachiocephalic and left common carotid artery. Naber et al61 described the ﬁrst-in-man use of this novel device in 40 patients undergoing TAVI with evidence of reduction of procedural cerebral embolic burden.
The TriGuard Cerebral Protection Device (Keystone Heart, Israel, formerly SMT R&D) works as a debris deﬂector instead of a debris collector. A similar device is the Embrella Embolic Deﬂector (Edwards Lifesciences, Irvine, California, USA). Both Embrella and TriGuard have a protective shield that deﬂects embolisms away from the cerebral arteries.
The SMT FIM (ﬁrst-in-man) feasibility study described the use of the SHEF device in the ﬁrst 15 patients62. The ongoing DEFLECT I (SMT Embolic Deﬂection CE Mark) study is expected to provide further evidence of the effectiveness of the device. First results have been presented at EuroPCR in May 2013 in Paris and show promising results. The maximum total lesion volume in DEFLECT I was 95% smaller than the maximum total lesion volume in reported studies (3.94 vs 70.3 cm3).
The human experience with Embrella comes from a small study of four patients with severe AS who underwent aortic balloon valvuloplasty or TAVI63. There were no procedural complications. The procedural safety, technical feasibility, and exploratory efﬁcacy of the Embrella device was studied in the ProTAVI-C pilot study at nine centers involving 54 patients. Use of the Embrella deﬂector system during TAVI was feasible and safe with minimal procedural complications. There were no procedural strokes or impairment of neurocognitive function. Though there was cerebral microembolization in all patients, there was a potential decrease in cerebral lesion volume. A phase 2 randomized study is being conducted to measure the reduction of new cerebral lesion volume.
Aortic valve interventions:
- There is strong evidence demonstrating that TAVR is effective compared to medical therapy.
- TAVR is non-inferior to surgical AVR in high risk patients, it has several advantages, but has been associated with a slightly higher stroke risk.
- Ongoing and planned trials looking at the comparative effect of TAVR and AVR in intermediate risk patients are likely to show non-inferiority and may further increase the use of TAVR.
Approximately 5-10% of all hypertensive patients are resistant to medical treatment, deﬁned as blood pressures >140/90 mm Hg or >130-139/80-85 mm Hg in diabetic patients, or >130/80 mm Hg in patients with chronic kidney disease (CKD) in the presence of ≥3 antihypertensives of different classes, including a diuretic, at maximal or the highest tolerated dose. However, ‘resistance’ is probably not rarely caused by malcompliance. On the other hand, drug intolerance or side effects are not rare and can be a challenge in medical blood pressure management. The development of catheter based radiofrequency ablation of the renal sympathetic nervous ﬁbres is a highly promising new approach.
In 2009, a European–Australian proof-of-principle study, the non-randomised Simplicity HTN-1, was published; it was performed on 50 patients with resistant hypertension (ie, systolic blood pressure ≥160 mm Hg on three or more antihypertensive medications, including a diuretic)64. Five of the patients who were not anatomically eligible for the denervation procedure were used as controls. After this radiofrequency ablation catheter procedure (Symplicity, Ardian Inc, Palo Alto, California, USA), the blood pressure in these 45 patients dropped signiﬁcantly over a period of 12 months (Figure 3).
An expanded cohort of 153 patients with resistant hypertension was studied in the Simplicity HTN-1 study65. The patients were treated with catheter based renal sympathetic denervation at 19 centers in Australia, Europe, and the USA. They showed a substantial and sustained reduction of blood pressure over a follow up of ≥2 years without any signiﬁcant adverse effects. Simplicity HTN-1 was a feasibility study and had no control group. The subsequent Simplicity HTN-2 trial randomized 106 patients to renal denervation or control66. At 6 months, the blood pressure in the treatment group was signiﬁcantly lower. After the 6-month end point, a crossover was done and renal denervation in control patients was allowed67. In the initial renal denervation group, the signiﬁcant reduction in mean blood pressure at 6 months (-32 mmHg) was sustained at 12 months (-28 mmHg). At 6 months, the control group had shown an increase in blood pressure from 182.8±16.3 to 190.0±19.6 mmHg. Those among this control group who underwent renal denervation as crossover had a signiﬁcant fall in their blood pressure at 6 months after the procedure (-24 mmHg; p <0.001 for difference from before the procedure). This substantiated the safety and efﬁcacy of renal denervation via controlled radiofrequency ablation.
The Simplicity HTN-2 study did not report on the 24 h blood pressure monitoring. It was not a blinded study design. These methodological issues are being
addressed in the Simplicity HTN-3 study67. It is a multicenter, single blind, randomized controlled trial where patients are being randomized to bilateral renal denervation with the Simplicity catheter or to a sham procedure. One of the important secondary end points of the study is the change in 24 h blood pressure.
The Simplicity renal denervation device has also been tried in other patient groups, such as in a pilot study of patients with resistant hypertension and moderate to severe (stage 3 or 4) CKD68. It was found to be safe and effective. The Simplicity HF study is currently enrolling 40 patients for a pilot study to evaluate the effects of renal denervation in heart failure patients. In the real world setting, the Global Simplicity Registry is expected to enrol 5000 patients in 200 sites worldwide. The registry had enrolled 617 patients by 25 May 2013. Based on preliminary data presented at the EuroPCR 2013, there have been signiﬁcant drops in in-ofﬁce blood pressure and 24 h blood pressure. These reductions are, however, smaller than those seen in clinical trials.
At the EuroPCR 2013, interim data from the ﬁrst 41 patients treated with the alternative Vessix renal denervation system in its REDUCE-HTN study were presented69. At 6 months, there was a signiﬁcant reduction in blood pressure (-27.6 mmHg; p <0.0001). In those patients for whom 12-month data were available, there was a sustained reduction in systolic blood pressure (-28.4 mmHg). There were no device related adverse events or procedural complications and the procedure time was short.
The Enligh HTN multielectrode renal denervation catheter (St Jude Medical) has been tried in 46 patients who were then followed up for 1 year70. Most patients (80%) responded to therapy (had at least 10 mmHg reduction in mean blood pressure). The mean reduction in blood pressure at 12 months was 27 mmHg. The multielectrode device reduces the renal denervation time and is also less painful to patients. Other devices with a multimode approach include the Covidien One-Shot device and a modiﬁcation of the Simplicity device called the Spyral device.
Currently, renal denervation is considered an adjunctive therapy to medical treatment, not a replacement, since the average number of patients taking antihypertensive medications has not declined in the trials in spite of the reduction in mean blood pressure following renal denervation70.
Although there is a lot of excitement about this new modality of treatment for resistant hypertension, there are concerns about the diffuse renal artery constriction and tissue damage at the ablation site, with edema and thrombus formation that may occur following renal nerve ablation71. Dual antiplatelet therapy may therefore be needed during the procedure. Even though renal denervation has been tried in patients with CKD68, patients with high grades of renal insufﬁciency should only be treated and systematically followed in clinical trials. It should also not be tried in anatomically unsuitable renal arteries (diameter <4 mm; length <20 mm; ﬁbromuscular dysplasia; signiﬁcant renal artery stenosis) or in cases of secondary and treatable causes of hypertension72. We also have to be aware that there are no data on the impact of renal denervation on clinical outcomes at this stage. Its use should therefore be restricted to patients with severe, resistant hypertension and it should be regarded as an adjunctive and not an alternative therapy to antihypertensive drugs.
- Renal denervation is a promising approach to treat resistant hypertension, its effect on blood pressure reduction is impressive, but future studies need to prove that this translates into improved clinical outcomes.
- Similar to TAVR, it is likely that the indication for this procedure will further expand to non-resistant hypertension and to other areas such as heart failure, rate control for AF, etc.
While there is clearly signiﬁcant technological progress in percutaneous coronary interventions73, the expanding options to treat non-coronary cardiac disease with catheter based techniques are revolutionary. Several of these procedures have been developed for very high surgical risk or ‘no option’ patients, such as TAVR, but are increasingly used in high risk or even intermediate risk patients as a less invasive alternative to surgery. The fast technological progress, increasing understanding, and improvements in the operators’ experience will further expand the indications for these procedures to lower risk patients and for applications for other indications. Renal denervation, as an example, may show beneﬁt in patients with heart failure or for rate control in AF.
Contributors: PM drafted the manuscript. OF revised the manuscript critically for intellectual content. AJL revised the manuscript critically for intellectual content. All three authors contributed signiﬁcantly to this paper and have approved the ﬁnal version.
Competing interests: None.
Provenance and peer review Commissioned: externally peer reviewed.
1. Meier P, Timmis A. Almanac 2012: interventional cardiology. Anadolu Kardiyol Derg 2012;13:91-101.
2. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial ﬁbrillation: the Framingham Heart Study. Circulation 2004;110:1042-6.
3. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial ﬁbrillation: the task force for the management of atrial ﬁbrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369-429.
4. Gallagher AM, Rietbrock S, Plumb J, et al. Initiation and persistence of warfarin or aspirin in patients with chronic atrial ﬁbrillation in general practice: do the appropriate patients receive stroke prophylaxis? J Thromb Haemost 2008;6:1500-6.
5. Garcia-Fernandez MA, Perez-David E, Quiles J, et al. Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. J Am Coll Cardiol 2003;42:1253-8.
6. MEMBERS WC, Bonow RO, Carabello BA, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118:e523-661.
7. Khattab AA, Meier B. Transcatheter left atrial appendage exclusion, gold or fool’s gold? Eur Heart J Suppl 2010;12:E35-40.
8. Sousa JE, Costa MA, Tuzcu EM, et al. New frontiers in interventional cardiology. Circulation 2005;111:671-81.
9. Munkholm-Larsen S, Cao C, Yan TD, et al. Percutaneous atrial appendage occlusion for stroke prevention in patients with atrial ﬁbrillation: a systematic review. Heart 2012;98:900-7.
10. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial ﬁbrillation: a randomised non-inferiority trial. Lancet 2009;374:534-42.
11. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial ﬁbrillation: 2.3-year follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720-9.
12. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011;123:417-24.
13. Massumi A, Chelu MG, Nazeri A, et al. Initial experience with a novel percutaneous left atrial appendage exclusion device in patients with atrial ﬁbrillation, increased stroke risk, and contraindications to anticoagulation. Am J Cardiol 2013;111:869-73.
14. Viles-Gonzalez JF, Kar S, Douglas P, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial ﬁbrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923-9.
15. Bass JL. Transcatheter occlusion of the left atrial appendage–experimental testing of a new Amplatzer device. Catheter Cardiovasc Interv 2010;76:181-5.
16. Fox BD, Kahn SR, Langleben D, et al. Efﬁcacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ 2012;345:e7498.
17. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial ﬁbrillation: an update of the 2010 ESC guidelines for the management of atrial ﬁbrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47.
18. Iung B, Vahanian A. Degenerative calciﬁc aortic stenosis: a natural history. Heart 2012;98:iv7-13.
19. Alﬁeri O, Denti P. Alﬁeri stitch and its impact on mitral clip. Eur J Cardiothorac Surg 2011;39:807-8.
20. Delgado V, Kapadia S, Marsan NA, et al. Multimodality imaging before, during, and after percutaneous mitral valve repair. Heart 2011;97: 1704-14.
21. Feldman T, Wasserman HS, Herrmann HC, et al. Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST phase I clinical trial. J Am Coll Cardiol 2005;46:2134-40.
22. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395-406.
23. Whitlow PL, Feldman T, Pedersen WR, et al. Acute and 12-month results with catheter-based mitral valve leaﬂet repair: the EVEREST II (Endovascular Valve Edge-to-Edge Repair) high risk study. J Am Coll Cardiol 2012;59:130-9.
24. Feldman T, Kar S, Rinaldi M, et al. Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol 2009;54:686-94.
25. Tamburino C, Ussia GP, Maisano F, et al. Percutaneous mitral valve repair with the MitraClip system: acute results from a real world setting. Eur Heart J 2010;31:1382-9.
26. Sürder D, Pedrazzini G, Gaemperli O, et al. Predictors for efﬁcacy of percutaneous mitral valve repair using the MitraClip system: the results of the MitraSwiss registry. Heart 2013;99:1034-40.
27. Kar S, Rinaldi M, Lim DS, et al. EVEREST II REALISM: a continued access study to evaluate the safety and effectiveness of the MitraClip device: demographics and procedural outcomes. Society for Cardiovascular Angiography and Interventions (SCAI) 2011 Scientiﬁc Sessions; Baltimore, 2011.
28. Rinaldi MJ, Kar S, Lim DS, et al. EVEREST II REALISM: a continued access study to evaluate the safety and effectiveness of the MitraClip device: analysis of a 6 month patient cohort. Society for Cardiovascular Angiography and Interventions (SCAI) 2011 Scientiﬁc Sessions; Baltimore, 2011.
29. Sarkar K, Ussia GP, Cammalleri V, et al. Quality of life of high risk patients following percutaneous mitral valve repair with the MitraClip system. Society for Cardiovascular Angiography and Interventions (SCAI) 2011 Scientiﬁc Sessions; Baltimore, 2011.
30. Gaemperli O, Moccetti M, Surder D, et al. Acute haemodynamic changes after percutaneous mitral valve repair: relation to mid-term outcomes. Heart 2012;98:126-32.
31. Samad Z, Kaul P, Shaw LK, et al. Impact of early surgery on survival of patients with severe mitral regurgitation. Heart 2011;97:221-4.
32. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005-11.
33. Rosenhek R. Almanac 2011: valvular heart disease. The national society journals present selected research that has driven recent advances in clinical cardiology. Heart 2011;97:2007-17.
34. Sinning J-M, Werner N, Nickenig G, et al. Transcatheter aortic valve implantation: the evidence. Heart 2012;98:iv65-72.
35. Agnihotri A. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: executive summary. J Thorac Cardiovasc Surg 2012;144:534-7.
36. Watt M, Mealing S, Eaton J, et al. Cost-effectiveness of transcatheter aortic valve replacement in patients ineligible for conventional aortic valve replacement. Heart 2012;98:370-6.
37. Binder RK, Webb JG. TAVI: from home-made prosthesis to global interventional phenomenon. Heart 2012;98:iv30-6.
38. Grant SW, Devbhandari MP, Grayson AD, et al. What is the impact of providing a transcatheter aortic valve implantation service on conventional aortic valve surgical activity: patient risk factors and outcomes in the ﬁrst 2 years. Heart 2010;96:1633-7.
39. Malaisrie SC, Tuday E, Lapin B, et al. Transcatheter aortic valve implantation decreases the rate of unoperated aortic stenosis. Eur J Cardiothorac Surg 2011;40:43-8.
40. Thomas M, Schymik G, Walther T, et al. Thirty-day results of the SAPIEN aortic bioprosthesis European outcome (SOURCE) registry: a European registry of transcatheter aortic valve implantation using the Edwards SAPIEN Valve. Circulation 2010;122:62-9.
41. Thomas M, Schymik G, Walther T, et al. One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: the European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 2011; 124:425-33.
42. Dworakowski R, Wendler O. Optimal pain management after aortic valve implantation: an opportunity to improve outcomes after transapical access in the future? Heart 2012;98:1541–2.
43. Stortecky S, Buellesfeld L, Wenaweser P, et al. Transcatheter aortic valve implantation: the procedure. Heart 2012;98:iv44-51.
44. Amat-Santos IJ, Dumont E, Villeneuve J, et al. Effect of thoracic epidural analgesia on clinical outcomes following transapical transcatheter aortic valve implantation. Heart 2012;98:1583-90.
45. Bourantas CV, Farooq V, Onuma Y, et al. Transcatheter aortic valve implantation: new developments and upcoming clinical trials. EuroIntervention 2012;8:617-27.
46. Mussardo M, Latib A, Chieffo A, et al. Periprocedural and short-term outcomes of transfemoral transcatheter aortic valve implantation with the Sapien XT as compared with the Edwards Sapien valve. JACC Cardiovasc Interv 2011;4:743–50.
47. Svensson LG, Tuzcu M, Kapadia S, et al. A comprehensive review of the PARTNER trial. J Thorac Cardiovasc Surg 2013;145:S11-16.
48. Hahn RT, Pibarot P, Stewart WJ, et al. Comparison of transcatheter and surgical aortic valve replacement in severe aortic stenosis: a longitudinal study of echo parameters in cohort A of the PARTNER trial. J Am Coll Cardiol 2013;61:2514-21.
49. Kempny A, Diller G-P, Kaleschke G, et al. Impact of transcatheter aortic valve implantation or surgical aortic valve replacement on right ventricular function. Heart 2012;98:1299-304.
50. Mesa D, Castillo F, Ruiz Ortiz M, et al. Impact of transcatheter aortic valve implantation or surgical aortic valve replacement on right ventricular function. Heart 2013;99:286.
51. Dworakowski R, Wendler O, Bhan A, et al. Successful transcatheter aortic valve implantation (TAVI) is associated with transient left ventricular dysfunction. Heart 2012;98:1641-6.
52. Abdel-Wahab M, Zahn R, Horack M, et al. Aortic regurgitation after transcatheter aortic valve implantation: incidence and early outcome. Results from the German transcatheter aortic valve interventions registry. Heart 2011;97:899-906.
53. Gripari P, Ewe SH, Fusini L, et al. Intraoperative 2D and 3D transoesophageal echocardiographic predictors of aortic regurgitation after transcatheter aortic valve implantation. Heart 2012;98:1229-36.
54. Neragi-Miandoab S, Skripochnik E, Michler RE. Recently patented and widely used valves for transcatheter aortic valve implantation. Recent Pat Cardiovasc Drug Discov 2012;7:196-205.
55. Piazza N, Grube E, Gerckens U, et al. Procedural and 30-day outcomes following transcatheter aortic valve implantation using the third generation (18 Fr) corevalve revalving system: results from the multicentre, expanded evaluation registry 1-year following CE mark approval. EuroIntervention 2008;4:242-9.
56. Tamburino C, Capodanno D, Ramondo A, et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 2011;123:299-308.
57. Bagur R, Manazzoni JM, Dumont E, et al. Permanent pacemaker implantation following isolated aortic valve replacement in a large cohort of elderly patients with severe aortic stenosis. Heart 2011;97:1687-94.
58. Fairbairn TA, Mather AN, Bijsterveld P, et al. Diffusion-weighted MRI determined cerebral embolic infarction following transcatheter aortic valve implantation: assessment of predictive risk factors and the relationship to subsequent health status. Heart 2012;98:18-23.
59. Prendergast BD, Naber CK, Popma JJ. Transatlantic perspectives on TAVI: from essential infrastructure and integration to expansion, research and development. Heart 2012;98:iv37-43.
60. Astarci P, Glineur D, Kefer J, et al. Magnetic resonance imaging evaluation of cerebral embolization during percutaneous aortic valve implantation: comparison of transfemoral and trans-apical approaches using Edwards Sapiens valve. Eur J Cardiothorac Surg 2011;40:475-9.
61. Naber CK, Ghanem A, Abizaid AA, et al. First-in-man use of a novel embolic protection device for patients undergoing transcatheter aortic valve implantation. EuroIntervention 2012;8:43-50.
62. Onsea K, Agostoni P, Samim M, et al. First-in-man experience with a new embolic deﬂection device in transcatheter aortic valve interventions. EuroIntervention 2012;8:51-6.
63. Nietlispach F, Wijesinghe N, Gurvitch R, et al. An embolic deﬂection device for aortic valve interventions. JACC Cardiovasc Interv 2010;3: 1133-8.
64. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275-81.
65. Investigators SH. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911-17.
66. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 trial): a randomised controlled trial. Lancet 2010;376:1903-9.
67. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 2012;126:2976-82.
68. Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol 2012;23:1250-7.
69. Schofer J. REDUCE-HTN trial. EuroPCR. Paris, France: Euro PCR, 2013.
70. Worthley SG. EnligHTN-1: BP drops durable, safe at one year, as renal-denervation mania grows. EuroPCR. Paris, France: heartwire, 2013.
71. Templin C, Jaguszewski M, Ghadri JR, et al. Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: pre- and post-procedural comparison with the Simplicity catheter system and the EnligHTN™ multi-electrode renal denervation catheter. Eur Heart J 2013 Apr 25. [Epub ahead of print] doi:10.1093/eurheartj/eht141
72. Ewen S, Ukena C, Böhm M, et al. Percutaneous renal denervation: new treatment option for resistant hypertension and more? Heart 2013.
73. Meier P, Timmis A. Almanac 2012: interventional cardiology: the national society journals present selected research that has driven recent advances in clinical cardiology. Heart 2012;98:1701-9.