Clin Res Cardiol DOI 10.1007/s00392-014-0733-z
CLINICAL TRIAL UPDATES AND HOTLINE SESSIONS
Hotline update of clinical trials and registries presented at the American College of Cardiology Congress 2014 Dirk Westermann • Reinhold Kreutz Claudius Jacobshagen
•
Received: 5 May 2014 / Accepted: 30 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract This article provides information and commentaries on trials which were presented at the Hotline and Clinical Trial Update Sessions during the Late Breaking Clinical Trial Sessions at the 63rd annual meeting of the American College of Cardiology in Washington, USA, from 29th to 31st March 2014. This article gives an overview on a number of novel clinical trials in the field of cardiovascular medicine, which were presented. Comprehensive summaries have been generated from the oral presentation and the webcasts of the American College of Cardiology, similar to as previously reported and should provide the readers with the most comprehensive information of relevant publications. The discussed studies are US CoreValve, Choice, Symplcity-HTN-3, GRS, ZEUS, GIPS-III, HEAT-PPCI, COPR-2, MSC-HF, POISE-2, SIRS. The data were presented by leading experts in the field. Keywords US CoreValve Symplcity-HTN-3 GIPS-III COPR-2 POISE-2
D. Westermann (&) Department of General and Interventional Cardiology, University Heart Center Hamburg Eppendorf, Martinistr. 52, 20246 Hamburg, Germany e-mail: [email protected] R. Kreutz Department of Clinical Pharmacology and Toxicology, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany C. Jacobshagen Clinic for Cardiology and Pneumology, Georg-AugustUniversity, Go¨ttingen, Germany
US CoreValve Pivotal Trial Transcatheter aortic-valve replacement (TAVR) with a balloon-expandable device improves survival, as compared with medical therapy, in patients with severe aortic stenosis who cannot undergo surgery [1]. Balloon-expandable TAVR and surgical AVR are associated with similar survival rates at 1 year among patients considered to be at high surgical risk [2]. The US CoreValve Pivotal Trial is a prospective, randomized multicenter trial comparing TAVR using the self-expanding Medtronic CoreValve device with surgical AVR in patients with severe aortic stenosis and increased risk of death during surgery. 795 patients were randomly assigned in 45 centers in the United States in a 1:1 ratio to the TAVR group or to the surgical group. The primary endpoint was rate of death from any cause. In 323 patients the valve was delivered via the iliofemoral route, in 67 patients via non-iliofemoral access. In the as-treated analysis, the rate of death from any cause at 1 year was significantly lower in the TAVR group than in the surgical group (14.2 vs. 19.1 %, P = 0.04 for superiority). Similar results were seen in the intention-to-treat analysis. Regarding secondary endpoints, bleeding events and acute kidney injury were significantly lower in the TAVR group, whereas vascular complications and permanent pacemaker implantations were significantly lower in the surgical group. The periprocedural stroke rate was similar. Echocardiographic indexes of valve stenosis, functional status, and quality of life were noninferior with TAVR. Interestingly, 76.2 % of patients with moderate or severe paravalvular regurgitation at discharge had mild or no regurgitation at 1 year. In conclusion, this is the first randomized study that demonstrates a survival benefit of TAVR compared to surgical AVR after 1 year [3]. (Presenter: David H Adams, Mount Sinai Medical Center, New York, NY, USA) Fig. 1.
123
Clin Res Cardiol Fig. 1 Primary 1-year outcome of the CoreValve US Pivotal Trial showing improved survival after TAVR compared to surgical valve replacement
30
SAVR TAVR
25
Mortality (%)
p=0,04 for superiority 20
19,1 %
15
14,2 %
10
4,5 %
5
3,3 % 0 0
1
2
3
4
5
6
7
8
9
10
11
12
Time after procedure (month) No. at risk SAVR TAVR
357 390
341 377
297 353
274 329
TAVR = Transcatheter aortic valve replacement ; SAVR = surgical valve replacement
Choice Transcatheter aortic-valve replacement has been shown to be an effective treatment option for high-risk patients with severe aortic stenosis [4, 5]. The Choice Trial is the first head-to-head comparison of these two devices. 121 patients were randomly assigned to receive a ballonexpandable device (Edwards Sapien XT) and 120 were assigned to receive a self-expandable valve (Medtronic CoreValve) in five centers in Germany. The primary endpoint was device success, defined by the Valve Academic Research Consortium (VARC) as successful vascular access and deployment of the device and retrieval of the delivery system, correct position of the device, and performance of the heart valve without moderate or severe regurgitation. At 30 days, device success was seen in 95.9 % in the balloon-expandable valve group, compared with 77.5 in the self-expandable valve group (relative risk 1.24, 95 % CI 1.12–1.37, P \ 0.001). The key driver of this difference was the fewer frequency of moderate or severe valvular regurgitation, seen in 4.1 % of Sapientreated patients compared with 18.3 % of CoreValve patients (relative risk 0.23, 95 % CI 0.09–0.58, P = 0.03) and the less frequent need for implanting more than 1 valve (0.8 vs. 5.8 %, P = 0.0,3). Bleeding and vascular complications were not significantly different between groups. As seen in every other trial, new pacemaker use was significantly higher in the CoreValve device group (37.6 vs. 17.3 %, P = 0.001). However, pacemaker rates in both groups are extraordinary high and much higher than in the US CoreValve Pivotal Trial mentioned above, which is an important field of research [6, 7]. Cardiovascular mortality at 30 days was similar between groups.
123
In conclusion, this first head-to-head comparison of the two most often used TAVR devices resulted in a greater rate of device success for the balloon-expandable valve [8]. Long-term follow-up should be awaited to determine whether differences in device success will translate into a clinically relevant overall benefit for the Sapien device. Future developments are eagerly awaited in this important field and updated devices will certainly improve outcome furthermore [9–15]. This was presented by Mohamed Abdel-Wahap.
Symplicity-HTN-3 The study sponsor of the Symplicity-HTN-3 announced the trial missed its primary efficacy end point in January 2014 already. Nevertheless, the full study results were presented at the ACC 2014 for the first time. Symplicity-HTN-3 randomized 535 patients from 88 US-based study sites with treatment-resistant hypertension with office SBP of over 160 mmHg (three times confirmed) to receive renal denervation or a sham procedure in a blinded 2:1 fashion. Patients had to be on a stable medication regimen including three different class antihypertensive drugs (fully tolerated doses) including one diuretic. Last medication change was allowed 2 weeks prior to screening visit. Patients with an ABPM 24 h average blood pressure \135 mmHg were excluded. Patients were randomized to receive denervation or sham control only after renal angiography, so all patients received similar procedural treatment. Therefore, this represents the first blinded renal denervation trial. A questioner controlled blinding and certified successful blinding at hospital discharge and at 6 months. While the treatment
Clin Res Cardiol
was safe (major adverse events 1.4 vs. 0.6 %, ns) the prespecified superiority margin of 5 mmHg blood pressure lowering was not reached (-2.39, 95 % CI -6.89 to 2.12). Interestingly, there was a significant blood pressure reduction in both groups compared to baseline, but no significant changes between both groups (-14.1 ± 23.9 vs. -11.7 ± 25.9, ns) were observed. This was verified by ABPM 24 h readings with similar results. When patients were stratified to blood pressure tertiles, there was also no sign of superiority in patients with higher or lower blood pressures. While many confounders may explain these results (e.g., the medication changes just 2 weeks prior enrollment as well as a possible Hawthorne effect with regard to medication adherence) and the number of ablations performed in each center were relatively low, this study presented and published [16] by Deepak Bath reminds us that renal denervation is not a clinically established therapy yet and new research is needed in this field (Figs. 2, 3).
The Global Symplicity Register Michael Bo¨hm presented the results of the Global Symplicity Register (GSR). While the goal of GSR is to include more than 5,000 patients, at this ACC the data of the first 1,000 patients were presented. Similarly to the SymplicityHTN-3 study, the GSR showed a good safety profile of renal denervation (e.g., vascular complication rate 0.4 %). Interestingly, when the results with regard to efficacy were compared to the HTN-3 trial, it could be shown that in similar patients (SBP \160 mmHg and 3 fully tolerated antihypertensive drugs) the blood pressure lowering was more pronounced in the register with 17.2 mmHg compared to the HTN-3 trial. Moreover, 50 % of the patients had a blood pressure of drop more than 20 mmHg. Obviously, a register cannot control for other effects, so there was no sham arm included. The GSR is an important complimentary information about renal denervation and further helps us to understand the possible effects of
Δ = -2,39 (95 % Kl, -6,89 – 2,12) p = 0,26*
Fig. 2 Efficacy outcome of the Symplicity-HTN-3 trial showing no increased blood pressure reduction after renal denervation compared to SHAM procedure
Δ = -14,1 ± 23,9 p
CLINICAL TRIAL UPDATES AND HOTLINE SESSIONS
Hotline update of clinical trials and registries presented at the American College of Cardiology Congress 2014 Dirk Westermann • Reinhold Kreutz Claudius Jacobshagen
•
Received: 5 May 2014 / Accepted: 30 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract This article provides information and commentaries on trials which were presented at the Hotline and Clinical Trial Update Sessions during the Late Breaking Clinical Trial Sessions at the 63rd annual meeting of the American College of Cardiology in Washington, USA, from 29th to 31st March 2014. This article gives an overview on a number of novel clinical trials in the field of cardiovascular medicine, which were presented. Comprehensive summaries have been generated from the oral presentation and the webcasts of the American College of Cardiology, similar to as previously reported and should provide the readers with the most comprehensive information of relevant publications. The discussed studies are US CoreValve, Choice, Symplcity-HTN-3, GRS, ZEUS, GIPS-III, HEAT-PPCI, COPR-2, MSC-HF, POISE-2, SIRS. The data were presented by leading experts in the field. Keywords US CoreValve Symplcity-HTN-3 GIPS-III COPR-2 POISE-2
D. Westermann (&) Department of General and Interventional Cardiology, University Heart Center Hamburg Eppendorf, Martinistr. 52, 20246 Hamburg, Germany e-mail: [email protected] R. Kreutz Department of Clinical Pharmacology and Toxicology, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany C. Jacobshagen Clinic for Cardiology and Pneumology, Georg-AugustUniversity, Go¨ttingen, Germany
US CoreValve Pivotal Trial Transcatheter aortic-valve replacement (TAVR) with a balloon-expandable device improves survival, as compared with medical therapy, in patients with severe aortic stenosis who cannot undergo surgery [1]. Balloon-expandable TAVR and surgical AVR are associated with similar survival rates at 1 year among patients considered to be at high surgical risk [2]. The US CoreValve Pivotal Trial is a prospective, randomized multicenter trial comparing TAVR using the self-expanding Medtronic CoreValve device with surgical AVR in patients with severe aortic stenosis and increased risk of death during surgery. 795 patients were randomly assigned in 45 centers in the United States in a 1:1 ratio to the TAVR group or to the surgical group. The primary endpoint was rate of death from any cause. In 323 patients the valve was delivered via the iliofemoral route, in 67 patients via non-iliofemoral access. In the as-treated analysis, the rate of death from any cause at 1 year was significantly lower in the TAVR group than in the surgical group (14.2 vs. 19.1 %, P = 0.04 for superiority). Similar results were seen in the intention-to-treat analysis. Regarding secondary endpoints, bleeding events and acute kidney injury were significantly lower in the TAVR group, whereas vascular complications and permanent pacemaker implantations were significantly lower in the surgical group. The periprocedural stroke rate was similar. Echocardiographic indexes of valve stenosis, functional status, and quality of life were noninferior with TAVR. Interestingly, 76.2 % of patients with moderate or severe paravalvular regurgitation at discharge had mild or no regurgitation at 1 year. In conclusion, this is the first randomized study that demonstrates a survival benefit of TAVR compared to surgical AVR after 1 year [3]. (Presenter: David H Adams, Mount Sinai Medical Center, New York, NY, USA) Fig. 1.
123
Clin Res Cardiol Fig. 1 Primary 1-year outcome of the CoreValve US Pivotal Trial showing improved survival after TAVR compared to surgical valve replacement
30
SAVR TAVR
25
Mortality (%)
p=0,04 for superiority 20
19,1 %
15
14,2 %
10
4,5 %
5
3,3 % 0 0
1
2
3
4
5
6
7
8
9
10
11
12
Time after procedure (month) No. at risk SAVR TAVR
357 390
341 377
297 353
274 329
TAVR = Transcatheter aortic valve replacement ; SAVR = surgical valve replacement
Choice Transcatheter aortic-valve replacement has been shown to be an effective treatment option for high-risk patients with severe aortic stenosis [4, 5]. The Choice Trial is the first head-to-head comparison of these two devices. 121 patients were randomly assigned to receive a ballonexpandable device (Edwards Sapien XT) and 120 were assigned to receive a self-expandable valve (Medtronic CoreValve) in five centers in Germany. The primary endpoint was device success, defined by the Valve Academic Research Consortium (VARC) as successful vascular access and deployment of the device and retrieval of the delivery system, correct position of the device, and performance of the heart valve without moderate or severe regurgitation. At 30 days, device success was seen in 95.9 % in the balloon-expandable valve group, compared with 77.5 in the self-expandable valve group (relative risk 1.24, 95 % CI 1.12–1.37, P \ 0.001). The key driver of this difference was the fewer frequency of moderate or severe valvular regurgitation, seen in 4.1 % of Sapientreated patients compared with 18.3 % of CoreValve patients (relative risk 0.23, 95 % CI 0.09–0.58, P = 0.03) and the less frequent need for implanting more than 1 valve (0.8 vs. 5.8 %, P = 0.0,3). Bleeding and vascular complications were not significantly different between groups. As seen in every other trial, new pacemaker use was significantly higher in the CoreValve device group (37.6 vs. 17.3 %, P = 0.001). However, pacemaker rates in both groups are extraordinary high and much higher than in the US CoreValve Pivotal Trial mentioned above, which is an important field of research [6, 7]. Cardiovascular mortality at 30 days was similar between groups.
123
In conclusion, this first head-to-head comparison of the two most often used TAVR devices resulted in a greater rate of device success for the balloon-expandable valve [8]. Long-term follow-up should be awaited to determine whether differences in device success will translate into a clinically relevant overall benefit for the Sapien device. Future developments are eagerly awaited in this important field and updated devices will certainly improve outcome furthermore [9–15]. This was presented by Mohamed Abdel-Wahap.
Symplicity-HTN-3 The study sponsor of the Symplicity-HTN-3 announced the trial missed its primary efficacy end point in January 2014 already. Nevertheless, the full study results were presented at the ACC 2014 for the first time. Symplicity-HTN-3 randomized 535 patients from 88 US-based study sites with treatment-resistant hypertension with office SBP of over 160 mmHg (three times confirmed) to receive renal denervation or a sham procedure in a blinded 2:1 fashion. Patients had to be on a stable medication regimen including three different class antihypertensive drugs (fully tolerated doses) including one diuretic. Last medication change was allowed 2 weeks prior to screening visit. Patients with an ABPM 24 h average blood pressure \135 mmHg were excluded. Patients were randomized to receive denervation or sham control only after renal angiography, so all patients received similar procedural treatment. Therefore, this represents the first blinded renal denervation trial. A questioner controlled blinding and certified successful blinding at hospital discharge and at 6 months. While the treatment
Clin Res Cardiol
was safe (major adverse events 1.4 vs. 0.6 %, ns) the prespecified superiority margin of 5 mmHg blood pressure lowering was not reached (-2.39, 95 % CI -6.89 to 2.12). Interestingly, there was a significant blood pressure reduction in both groups compared to baseline, but no significant changes between both groups (-14.1 ± 23.9 vs. -11.7 ± 25.9, ns) were observed. This was verified by ABPM 24 h readings with similar results. When patients were stratified to blood pressure tertiles, there was also no sign of superiority in patients with higher or lower blood pressures. While many confounders may explain these results (e.g., the medication changes just 2 weeks prior enrollment as well as a possible Hawthorne effect with regard to medication adherence) and the number of ablations performed in each center were relatively low, this study presented and published [16] by Deepak Bath reminds us that renal denervation is not a clinically established therapy yet and new research is needed in this field (Figs. 2, 3).
The Global Symplicity Register Michael Bo¨hm presented the results of the Global Symplicity Register (GSR). While the goal of GSR is to include more than 5,000 patients, at this ACC the data of the first 1,000 patients were presented. Similarly to the SymplicityHTN-3 study, the GSR showed a good safety profile of renal denervation (e.g., vascular complication rate 0.4 %). Interestingly, when the results with regard to efficacy were compared to the HTN-3 trial, it could be shown that in similar patients (SBP \160 mmHg and 3 fully tolerated antihypertensive drugs) the blood pressure lowering was more pronounced in the register with 17.2 mmHg compared to the HTN-3 trial. Moreover, 50 % of the patients had a blood pressure of drop more than 20 mmHg. Obviously, a register cannot control for other effects, so there was no sham arm included. The GSR is an important complimentary information about renal denervation and further helps us to understand the possible effects of
Δ = -2,39 (95 % Kl, -6,89 – 2,12) p = 0,26*
Fig. 2 Efficacy outcome of the Symplicity-HTN-3 trial showing no increased blood pressure reduction after renal denervation compared to SHAM procedure
Δ = -14,1 ± 23,9 p
