In Europe, moreso than in other countries in the world, we are to witness a dramatic surge in patients with cardiovascular disease over the next decades, because elderly patients are the fastest growing population in our healthcare system. By 2050, the number of people aged 65 and above is expected to grow by 70% and the number aged over 80, by 170% (1). This poses important challenges for the 21st century: to adapt our health systems to the needs of an ageing population with cardiovascular disease while finding the optimal (personalised) treatment strategy for the individual patient.
Severe aortic stenosis in elderly patients with multiple and complex comorbidities and who are unsuitable for surgical valve replacement is becoming increasingly prevalent. More than 30% of all patients with valvular heart disease do not undergo surgical valve replacement, mainly due to advanced age and the presence of multiple comorbidities (1). However, conservatively treated patients with severe aortic stenosis have a grave prognosis, which worsens with advanced age, left-ventricular dysfunction, heart failure, and renal failure (2).
In 1986, an experience with three elderly patients with acquired severe aortic valve stenosis treated with percutaneous transluminal balloon catheter aortic valvuloplasty (PTAV) was published by A. Cribier in The Lancet (3). Authors demonstrated that the transvalvular systolic pressure gradient was decreased after the procedure and valve opening had improved. They suggested that “PTAV is recommended as a simple alternative to aortic valve replacement in elderly and/or high-risk patients”. However, the clinical long-term course has since shown that pronounced functional improvement of aortic function following PTAV lasts only a short while and that in the long-term, post-PTAV patients show high rates of valve restenosis.
It was again A. Cribier who introduced transcatheter aortic valve implantation (TAVI) in 2002 which was followed by a series of single and multicentre experiences demonstrating that TAVI procedure as feasible, relatively safe, and successful in patients with severe morbidities and concomitant severe aortic stenosis. Currently, two valves are commercially available: the balloon-expandable Edwards SAPIEN prothesis (Edwards Lifesciences, Irvine, USA) and the Medtronic CoreValve (Medtronic CoreValve, Irvine, USA) self-expanding prosthesis. A detailed overview of indications, patient selection, interdisciplinary cooperation, procedure details, and description of the procedure has been provided by Vahanian et al. in the November 24th 2009 issue, Vol. 8, N°12 of the E-journal of Cardiology Practice.
The PARTNER Trial
1) Main findings
Here, we will focus on the recently published PARTNER trial, the first prospective, multicenter, randomised, active-treatment controlled clinical trial in patients with severe aortic stenosis who were not candidates for surgical aortic valve replacement.
Patients with severe symptomatic aortic stenosis (aortic valve area<0.8cm2, mean aortic valve gradient of ³40mmHg, or peak aortic jet velocity of ³4m/s) were enrolled. Two cohorts were defined:
- Cohort A - Patients in whom conventional aortic surgery was associated with high risk (STE score ³10%, or a predicted risk of death of 15% or higher 30 days after surgery due to co-morbidities), and
- Cohort B - Patients that were considered not suitable for conventional surgery due to a predicted probability of 50% or more of death or serious irreversible condition by 30 days after surgery. This evaluation of predicted mortality had to be confirmed by two surgeons.
The results for cohort B have been presented at the TCT Meeting 2010 and were published on September 22, 2010. The randomised trial of cohort A is ongoing. The primary endpoint of the PARTNER trial was the rate of death from any cause after at least 1 year. Interestingly, no cross-over between groups was permitted. The coprimary endpoint included time to death from any cause or time to occurrence of repeat hospitalisation due to valve- or procedure-related clinical complications.
Three thousand one hundrand and five patients with aortic stenosis were screened with approx. 12% undergoing randomisation and assignment to cohort B. One-hundred and seventy-nine patients were randomly assigned to TAVI using the balloon-expandable Edwards SAPIEN prosthesis (Edwards Lifesciences, Irvine, USA) and 179 patients to standard therapy which included PTAV. The median follow-up was 1.6 years.
Baseline characteristics were similar between treatment groups. Interestingly, the STS score showed a large variability (STS score 11.2±5.8 for TAVI, and 12.1±6.1 for Standard Therapy) with a number of patients having a STS Score below 10%. This was due to a large number of patients with porcelain aorta (15.1%), frailty (23.1%), chest wall irradiation (13.1%), or severe respiratory insufficiency with oxygen-dependence (23.5%), morbidities which are not mirrored in the STS score.
One hundred and seventy three patients were successfully implanted with an Edwards SAPIEN prosthesis (2 patients died before scheduled TAVI, in 2 patients femoral access was impossible, and 2 patients had a too large annulus for valve implantation). Procedural complications within 24h included 2 deaths (1.1%), 3 major strokes (1.7%), 1 valve embolisation (0.6%), and 2 (1.1%) multiple valve implantations.
Eighty-three point eight per cent of patients in the standard therapy arm received PTAV. However, of the 179 patients, 17 were treated surgically despite the initial decision for a conservative-only treatment option. Interestingly, 4 patients (2.2%) underwent TAVI at non-participating sites outside the US.
Thirty-day mortality from any cause was 5.0% in the TAVI group and 2.8% in the standard treatment group. However, at 1 year, the rate of death in the TAVI group was significantly lower compared to the standard therapy (30.7% vs. 50.7%, HR 0.55, 95%CI 0.40-0.74, p<0.001). The rate of cardiovascular death was similiarly reduced in the TAVI group compared to standard treatment (20.5% vs. 44.6%, HR 0.39, 95%CI 0.27-0.56, p<0.001). Major strokes tended to be more frequent in the TAVI group at 30 days (5.0% vs. 1.1%, p=0.06) and at 1 year (7.8% vs. 3.9%, p=0.18). No significant differences in outcome were observed in pre-specified sub-groups. Clinical improvement was significantly better in TAVI patients than in standard therapy patients in terms of NYHA classification and 6- minute walk test and corresponded with a significant reduction in mean aortic valve gradient and improved aortic valve area at 30 days and 1 year. Echocardiography revealed moderate to severe aortic regurgitation in 4.2% of TAVI patients and 15.2% in standard therapy after 1 year. Interestingly, conservatively treated patients showed only a mild reduction in the mean aortic gradient after PTAV which was at 1 year again identical with the pre-procedural gradient (43.2 ± 15.4mmHg initial, 33.1 ± 12.6 mmHg at 30 days; 44.3 ± 16.1mmHg at 1 year).
The results from the PARTNER trial demonstrate a superiority of transfemoral TAVI compared to standard therapy with a significantly reduced rate of death from any cause, death from cardiovascular causes, and the rate of repeat hospitalisation. In the first year, only five patients needed to be treated with TAVI to prevent one death, and only three patients needed to be treated to prevent either a death or repeat hospitalization.
2) Additional findings
There are numerous remarkable aspects of the trial which need separate attention:
We know from the experience in Europe, that the TAVI procedure is highly operator-dependent. Beginning a TAVI program implicates a learning curve for the whole team. The PARTNER trial showed a rate of death at 30 days among patients who underwent TAVI (5.0% in the intention-to-treat population, and 6.4% among patients who underwent TAVI) which did not differ significantly from that among patients who received standard therapy despite a high number of non-experienced centres.
Clearly, the number of neurological events, major vascular complications, and major bleeding events in the TAVI group was higher compared to the standard-therapy group. Previous studies have demonstrated that the neurological event rate might be even higher in TAVI patients when serial MRI investigations are performed (4). However, clinical apparent strokes with neurological impairment are relatively rare and novel protection devices may reduce the stroke rate in the near future.
Currently, we are still in need for long-term data on valve performance. All available data from single centre experiences with patients implanted at the beginning of the TAVI era indicate that the valves are still functionally intact after a follow-up of 5-8 years. However, the data is based on small patient numbers. Strong data of long-term valve function will not be available within the next 10 years.
TAVI was accompanied by the frequent occurrence of paravalvular regurgitation, which was usually mild. However, aortic regurgitation (AR) is still a major issue which has not been satisfactorily resolved for the TAVI procedure. Important factors influencing AR include mainly the degree of calcification and the implantation depth of the prosthesis. Further technical improvement including re-positionable of prostheses and the special focus on valve anatomy may reduce relevant AR after TAVI in the future.
The results of the conservatively treated patient cohort impressively underline the malignancy of the disease and the low effectiveness of a medial and/or PTAV-based therapy.