Henrik Nissen

Transcatheter Aortic Valve Implantation in Failed Bioprosthetic Surgical Valves

IMPORTANCE Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES Survival, stroke, and New York Heart Association functional class. RESULTS Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.

Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Valve Stenosis 1-Year Results From the All-Comers NOTION Randomized Clinical Trial

BACKGROUND Transcatheter aortic valve replacement (TAVR) is an option in certain high-risk surgical patients with severe aortic valve stenosis. It is unknown whether TAVR can be safely introduced to lower-risk patients. OBJECTIVES The NOTION (Nordic Aortic Valve Intervention Trial) randomized clinical trial compared TAVR with surgical aortic valve replacement (SAVR) in an all-comers patient cohort. METHODS Patients ≥ 70 years old with severe aortic valve stenosis and no significant coronary artery disease were randomized 1:1 to TAVR using a self-expanding bioprosthesis versus SAVR. The primary outcome was the composite rate of death from any cause, stroke, or myocardial infarction (MI) at 1 year. RESULTS A total of 280 patients were randomized at 3 Nordic centers. Mean age was 79.1 years, and 81.8% were considered low-risk patients. In the intention-to-treat population, no significant difference in the primary endpoint was found (13.1% vs. 16.3%; p = 0.43 for superiority). The result did not change in the as-treated population. No difference in the rate of cardiovascular death or prosthesis reintervention was found. Compared with SAVR-treated patients, TAVR-treated patients had more conduction abnormalities requiring pacemaker implantation, larger improvement in effective orifice area, more total aortic valve regurgitation, and higher New York Heart Association functional class at 1 year. SAVR-treated patients had more major or life-threatening bleeding, cardiogenic shock, acute kidney injury (stage II or III), and new-onset or worsening atrial fibrillation at 30 days than did TAVR-treated patients. CONCLUSIONS In the NOTION trial, no significant difference between TAVR and SAVR was found for the composite rate of death from any cause, stroke, or MI after 1 year. (Nordic Aortic Valve Intervention Trial [NOTION]; NCT01057173).

Transcatheter Aortic Valve Replacement for Degenerative Bioprosthetic Surgical Valves: Results from the Global Valve-in-Valve Registry

Background— Transcatheter aortic valve-in-valve implantation is an emerging therapeutic alternative for patients with a failed surgical bioprosthesis and may obviate the need for reoperation. We evaluated the clinical results of this technique using a large, worldwide registry. Methods and Results— The Global Valve-in-Valve Registry included 202 patients with degenerated bioprosthetic valves (aged 77.7±10.4 years; 52.5% men) from 38 cardiac centers. Bioprosthesis mode of failure was stenosis (n=85; 42%), regurgitation (n=68; 34%), or combined stenosis and regurgitation (n=49; 24%). Implanted devices included CoreValve (n=124) and Edwards SAPIEN (n=78). Procedural success was achieved in 93.1% of cases. Adverse procedural outcomes included initial device malposition in 15.3% of cases and ostial coronary obstruction in 3.5%. After the procedure, valve maximum/mean gradients were 28.4±14.1/15.9±8.6 mm Hg, and 95% of patients had ≤+1 degree of aortic regurgitation. At 30-day follow-up, all-cause mortality was 8.4%, and 84.1% of patients were at New York Heart Association functional class I/II. One-year follow-up was obtained in 87 patients, with 85.8% survival of treated patients. Conclusions— The valve-in-valve procedure is clinically effective in the vast majority of patients with degenerated bioprosthetic valves. Safety and efficacy concerns include device malposition, ostial coronary obstruction, and high gradients after the procedure. # Clinical Perspective {#article-title-38}Background— Transcatheter aortic valve-in-valve implantation is an emerging therapeutic alternative for patients with a failed surgical bioprosthesis and may obviate the need for reoperation. We evaluated the clinical results of this technique using a large, worldwide registry. Methods and Results— The Global Valve-in-Valve Registry included 202 patients with degenerated bioprosthetic valves (aged 77.7±10.4 years; 52.5% men) from 38 cardiac centers. Bioprosthesis mode of failure was stenosis (n=85; 42%), regurgitation (n=68; 34%), or combined stenosis and regurgitation (n=49; 24%). Implanted devices included CoreValve (n=124) and Edwards SAPIEN (n=78). Procedural success was achieved in 93.1% of cases. Adverse procedural outcomes included initial device malposition in 15.3% of cases and ostial coronary obstruction in 3.5%. After the procedure, valve maximum/mean gradients were 28.4±14.1/15.9±8.6 mm Hg, and 95% of patients had ⩽+1 degree of aortic regurgitation. At 30-day follow-up, all-cause mortality was 8.4%, and 84.1% of patients were at New York Heart Association functional class I/II. One-year follow-up was obtained in 87 patients, with 85.8% survival of treated patients. Conclusions— The valve-in-valve procedure is clinically effective in the vast majority of patients with degenerated bioprosthetic valves. Safety and efficacy concerns include device malposition, ostial coronary obstruction, and high gradients after the procedure.

Independent prognostic value of serum creatine kinase isoenzyme MB mass, cardiac troponin T and myosin light chain levels in suspected acute myocardial infarction: Analysis of 28 months of follow-up in 196 patients

OBJECTIVES We sought to determine the incidence and independent prognostic value of increased serum levels of sensitive serologic markers in patients in whom a conventionally diagnosed acute myocardial infarction had been ruled out. BACKGROUND Increased serum levels of creatine kinase (CK) isoenzyme MB mass and cardiac troponin T in patients with unstable angina pectoris are associated with a poor prognosis. METHODS We analyzed data from 196 consecutive patients with suspected acute myocardial infarction, which was later ruled out in 124. Increased serum levels of CK-MB mass, troponin T and myosin light chains were compared with clinical findings, ST-T wave abnormalities and presence of arrhythmias. RESULTS Of the patients in the noninfarction group, 28% had serum CK-MB mass > or = 6 micrograms/liter, 20% had troponin T > or = 0.20 micrograms/liter, and 26% had myosin light chains > or = 0.4 micrograms/liter (discrimination limits). The cardiac event rate (cardiac death, nonfatal acute myocardial infarction) within 28 months was significantly higher in patients in the noninfarction group with elevated marker levels (range 22% to 24%) than in patients with values below these discriminators (range 3% to 5%) but was not significantly different from that in patients with a definite diagnosis of acute myocardial infarction (29%). Further, significant predictors of cardiac events were previous myocardial infarction; myocardial infarction or angina pectoris, or both; previous congestive heart failure; ST-T wave abnormalities on admission; a transient ST-T wave shift on serial electrocardiograms (ECGs); recurrent chest pain; and occurrence of supraventricular or ventricular tachycardia, or both, during the 1st 48 h after admission. It was found that all three biochemical markers, in the main, convey independent prognostic information with respect to clinical findings and presence of arrhythmias but not ST-T wave abnormalities on admission or a transient ST-T wave shift on serial ECGs. CONCLUSIONS Increased serum levels of CK-MB mass, troponin T and myosin light chains all detect a subgroup of 25% of patients without acute myocardial infarction who have as poor a prognosis as that of patients with a definite diagnosis of acute myocardial infarction. All three biochemical markers provide similar important independent prognostic information with regard to clinical findings and arrhythmias but add no additional prognostic information once ECG ST-T wave changes are considered.

A prospective, randomised trial of transapical transcatheter aortic valve implantation vs. surgical aortic valve replacement in operable elderly patients with aortic stenosis: the STACCATO trial

AIMS In a prospective randomised trial we aimed to compare transapical transcatheter aortic valve implantation (a-TAVI) with surgical aortic valve replacement (SAVR) in operable elderly patients. METHODS AND RESULTS The study was designed as a randomised controlled trial of a-TAVI (Edwards SAPIEN heart valve system; Edwards Lifesciences, Irvine, CA, USA) vs. SAVR. Operable patients with isolated aortic valve stenosis and an age ≥75 years were included. The primary endpoint was the composite of all-cause mortality, cerebral stroke and/or renal failure requiring haemodialysis at 30 days. After advice from the Data Safety Monitoring Board, the study was prematurely terminated after the inclusion of 70 patients because of an excess of events in the a-TAVI group. The primary endpoint was met in five a-TAVI patients (two deaths, two strokes, and one case of renal failure requiring dialysis) vs. one stroke in the SAVR group (p=0.07). In the a-TAVI group, one patient was converted to SAVR because of an abnormally positioned heart, and four patients were re-operated with open heart surgery because of annulus rupture (n=1), severe paravalvular leakage (n=2), and blockage of the left coronary artery (n=1). In the SAVR group, one patient was converted to TAVI because of a large intra-thoracic goitre. CONCLUSIONS Given the limitations of a small prematurely terminated study, our results suggest that a-TAVI in its present form may be associated with complications and device success rates in low-risk patients similar or even inferior to those found in high-risk patients with aortic valve stenosis. This will probably change in the near future with improved catheter based devices and better pre-procedural assessment.

Cardiac troponin T and CK-MB mass release after visually successful percutaneous transluminal coronary angioplasty in stable angina pectoris

The incidence of cardiac troponin T (Tn-T) and creatine kinase (CK) isoenzyme MB mass release was studied in 23 patients with stable angina pectoris undergoing visually successful percutaneous transluminal coronary angioplasty (PTCA). Serial blood samples were drawn for measurement of serum Tn-T, CK-MB mass, total CK activity, CK-MB activity, and lactate dehydrogenase isoenzyme (LD-1). ST segment monitoring was carried out during PTCA and for the following 24 hours. None of the patients showed electrocardiographic (ECG) evidence of myocardial infarction. However, Tn-T was elevated in three patients (0.23 to 1.32 micrograms/L), and in these three and an additional three patients CK-MB mass was also elevated (7.0 to 27.5 micrograms/L). Total CK activity and LD-1 were only elevated in one of these six patients. None had elevated CK-MB activity. ST segment depression on ECG recording was not predictive of Tn-T or CK-MB mass release. Patients with elevated Tn-T or CK-MB mass did not differ with respect to demographic data, stenosis characteristics, or in the PTCA procedure. We conclude that CK-MB mass uncovers clinically and ambulatory electrocardiographically inapparent severe myocardial ischemia/minor myocardial damage (microembolization) in 26% (6 of 23) of patients after visually successful PTCA; 13% (3 of 23) had elevated Tn-T, indicating minor myocardial damage. The application of these markers in the future could be of considerable value for determining the efficacy of coronary angioplasty and atherectomy, as well as for drug therapy in connection with such procedures.

Two-Year Outcomes in Patients With Severe Aortic Valve Stenosis Randomized to Transcatheter Versus Surgical Aortic Valve Replacement The All-Comers Nordic Aortic Valve Intervention Randomized Clinical Trial

Background—The Nordic Aortic Valve Intervention (NOTION) trial was the first to randomize all-comers with severe native aortic valve stenosis to either transcatheter aortic valve replacement (TAVR) with the CoreValve self-expanding bioprosthesis or surgical aortic valve replacement (SAVR), including a lower-risk patient population than previous trials. This article reports 2-year clinical and echocardiographic outcomes from the NOTION trial. Methods and Results—Two-hundred eighty patients from 3 centers in Denmark and Sweden were randomized to either TAVR (n=145) or SAVR (n=135) with follow-up planned for 5 years. There was no difference in all-cause mortality at 2 years between TAVR and SAVR (8.0% versus 9.8%, respectively; P=0.54) or cardiovascular mortality (6.5% versus 9.1%; P=0.40). The composite outcome of all-cause mortality, stroke, or myocardial infarction was also similar (15.8% versus 18.8%, P=0.43). Forward-flow hemodynamics were improved following both procedures, with effective orifice area significantly more improved after TAVR than SAVR (effective orifice area, 1.7 versus 1.4 cm2 at 3 months). Mean valve gradients were similar after TAVR and SAVR. When patients were categorized according to Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) (<4% versus ≥4%), there was no statistically significant difference for TAVR and SAVR groups in the composite outcome for low-risk (14.7%, 95% confidence interval, 8.3–21.2 versus 16.8%; 95% confidence interval, 9.7–23.8; P=0.58) or intermediate-risk patients (21.1% versus 27.1%; P=0.59). Conclusions—Two-year results from the NOTION trial demonstrate the continuing safety and effectiveness of TAVR in lower-risk patients. Longer-term data are needed to verify the durability of this procedure in this patient population. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01057173.

Clinically applicable mutation screening in familial hypercholesterolemia

Mutations in the LDL receptor (LDLR) gene and the codon 3500 region of the apolipoprotein (apo) B‐100 gene result in the clinically indistinguishable phenotypes designated familial hypercholesterolemia (FH) and familial defective apo B‐100 (FDB), respectively. Introduction of genetic diagnosis in phenotypic FH families may remove the diagnostic inaccuracies known from traditional clinical/biochemical FH diagnosis and allow more differentiated prognostic evaluations and genetic counseling of FH/FDB families. Previous genetic screening methods for FH have, however, been too cumbersome for routine use, however. To overcome these problems, we designed a mutation screening assay based on the highly sensitive denaturing gradient gel electrophoresis (DGGE) technique. The setup allows within 24 hr to pinpoint if and where a potential mutation is located in the LDLR promoter, the 18 LDLR gene exons and corresponding intronic splice site sequences, or in the codon 3500 region of apo B‐100. The pinpointed region is subsequently sequenced. As an evaluation of the sensitivity, we demonstrated the ability of the assay to detect 27 different mutations or polymorphisms covering all the examined regions, except LDLR exon 16. In conclusion, a simple, but sensitive, clinically applicable mutation screening assay based on the DGGE principle may reveal the underlying mutation in most FH/FDB families and offer a tool for a more differentiated prognostic and therapeutic evaluation in FH/FDB.

Familial hypercholesterolaemia in Finland: common, rare and mild mutations of the LDL receptor and their clinical consequences

Familial hypercholesterolaemia (FH) is an autosomal co-dominantly inherited condition resulting from mutations of the low-density lipoprotein (LDL) receptor which occur in heterozygous form in approximately one in 500 individuals. Clinically, FH is characterized by 2-3-fold elevation of serum LDL cholesterol levels, accelerated development of atherosclerotic vascular disease, and, if untreated, shortened lifespan. The Finnish population, which represents a genetic isolate, offers exceptional possibilities for genetic-epidemiological studies on FH, as a handful of founder gene mutations account for the majority of FH cases in Finland. This review summarizes data from our FH studies carried out since 1985. We wish to emphasize the continuum of genotype-phenotype relationships, the importance of molecular diagnosis, the detection of novel risk factors of vascular disease, and innovations inhibiting cholesterol absorption for the modern treatment of FH.

Transcatheter Replacement of Failed Bioprosthetic Valves: Large Multicenter Assessment of the Effect of Implantation Depth on Hemodynamics After Aortic Valve-in-Valve

Background—Transcatheter valve implantation inside failed bioprosthetic surgical valves (valve-in-valve [ViV]) may offer an advantage over reoperation. Supra-annular transcatheter valve position may be advantageous in achieving better hemodynamics after ViV. Our objective was to define targets for implantation that would improve hemodynamics after ViV. Methods and Results—Cases from the Valve-in-Valve International Data (VIVID) registry were analyzed using centralized core laboratory assessment blinded to clinical events. Multivariate analysis was performed to identify independent predictors of elevated postprocedural gradients (mean ≥20 mm Hg). Optimal implantation depths were defined by receiver operating characteristic curve. A total of 292 consecutive patients (age, 78.9±8.7 years; 60.3% male; 157 CoreValve Evolut and 135 Sapien XT) were evaluated. High implantation was associated with significantly lower rates of elevated gradients in comparison with low implantation (CoreValve Evolut, 15% versus 34.2%; P=0.03 and Sapien XT, 18.5% versus 43.5%; P=0.03, respectively). Optimal implantation depths were defined: CoreValve Evolut, 0 to 5 mm; Sapien XT, 0 to 2 mm (0–10% frame height); sensitivities, 91.3% and 88.5%, respectively. The strongest independent correlate for elevated gradients after ViV was device position (high: odds ratio, 0.22; confidence interval, 0.1–0.52; P=0.001), in addition to type of device used (CoreValve Evolut: odds ratio, 0.5; confidence interval, 0.28–0.88; P=0.02) and surgical valve mechanism of failure (stenosis/mixed baseline failure: odds ratio, 3.12; confidence interval, 1.51–6.45; P=0.002). Conclusions—High implantation inside failed bioprosthetic valves is a strong independent correlate of lower postprocedural gradients in both self- and balloon-expandable transcatheter valves. These clinical evaluations support specific implantation targets to optimize hemodynamics after ViV.