,,
`
`"
`
`l~!
`
`Tht NEW ENGLAND JOURN1\L oJME.DlC!NE
`
`o_R_1c_11_N_._A_L_f_\_R_T_r_c_L_E_·
`
`~!I
`
`Two-Year Outcomes after Transcatheter
`or Surgical Aortic-Valve Replacement
`Susheel I( Koda!i. M.D., Mathew R. Williams, M.D., Craig R. Smith, M.D.,
`Lars G. Svensson, M.D .. Ph.D.,John G. Webb, M.D., Raj R. Makkar, M.D.,
`Gregory P. Fontana, M.D. Todd M. Dewey, M.D., Vinod H. Thourani, M.D.,
`Augusto D. Pichard, M.D., Michael Fischbein, M.D., Ph.D., Wilson Y Szeto, M.D.,
`Scott Lirn, M.D .. Kevin L. Greason, M.D., Paul S. Teirstein, M.D.,
`S. Chris Malaisrie, M.D., Pamela S. Douglas, M.D., Rebecca T. Hahn. M.D.,
`Brian Whisenant, M.D., Alan Zajarias, M.D., Duolao Wang, Ph.D.,
`JodiJ. Akin, M.S., William N. Anderson, Ph.D., and Martin B. Leon, M.D..
`for the PARTNER Trial Investigators'''
`
`1 J
`
`~
`
`ABSTRACT
`
`\ ~
`
`EXH\B\T J{ (l
`J/0-1~-/7 <fu~ I
`
`From Columbia University Medical Cen(cid:173)
`ter and New York Presbyterian Hospital
`(S.K.K., M.R.W., C.R.S., R.T.H., M.B.L.)
`and Lenox Hill Hospital (G.P.F.) - both
`in New York; Cleveland Clinic Foundation,
`Cleveland (L.G.S.); University of British
`Columbia and St. Paul's Hospital, Vancou(cid:173)
`ver, Canada U.G.W.); Cedars-Sinai Medi(cid:173)
`cal Center, Los Angeles (R.R.M.); Medi(cid:173)
`cal City Dallas, Dallas (T.M.D.); Emory
`University School of Medicine, Atlanta
`(V.H.T.); Washington Hospital Center,
`Washington, DC (A.D.P.); Stanford Uni(cid:173)
`versity Medical School, Palo Alto (M.F.),
`Scripps Clinic, La Jolla (P.S.T.), and Ed(cid:173)
`wards Lifesciences, Irvine U,J.A., W.N.A.)
`- all in California; Hospital of the Uni(cid:173)
`versity of Pennsylvania, Philadelphia
`(W.Y.S.); University of Virginia, Charlottes(cid:173)
`ville (S.L.); Mayo Clinic, Rochester, MN
`(K.L.G.); Northwestern University, Chi(cid:173)
`cago (S.C.M.); Duke University Medical
`Center, Durham, NC (P.S.D.); lntermoun(cid:173)
`tain Medical Center, Salt Lake City (B.W.);
`Washington University Medical School
`and Barnes-Jewish Hospital, St. Louis
`(A.Z.); and London School of Hygiene
`and Tropical Medicine, London (D.W.).
`Address reprint requests to Dr. Kodali at
`Columbia University Medical Center/
`New York Presbyterian Hospital, 161 Fort
`Washington Ave., 6th Fl., New York, NY
`10032, or at sk2427@columbia.edu.
`
`*The investigators, institutions, and re-
`search organizations participating in the
`Placement of Aortic Transcatheter Valves
`(PARTNER) trial are listed in the Supple(cid:173)
`mentary Appendix, available at NEJM.org.
`
`This article (10.1056/NEJMoal200384) was
`published on March 26, 2012, at NEJM.org.
`
`N EnglJ Med 2012;366:1686-95.
`Copyright © 2012 Massachusetts Medical Society.
`
`llACKGl?OUND
`The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among
`high-risk patients with aortic stenosis, the 1-year survival rates are similar with trans(cid:173)
`catheter aortic-valve replacement (TAVR) and surgical replacement. However, longer(cid:173)
`term follow-up is necessary to determine whether TAVR has prolonged benefits.
`
`METHODS
`At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis
`to undergo either surgical aortic-valve replacement or TAVR. All patients were fol(cid:173)
`lowed for at least 2 years, with assessment of clinical outcomes and echocardiographic
`evaluation.
`
`RESULTS
`The rates of death from any cause were similar in the TAVR and surgery groups
`(hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and
`at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the
`surgery group (P=0.78). The frequency of all strokes during follow-up did not differ
`significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23;
`P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical re(cid:173)
`placement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in
`the TAVR group and 12 in the surgery group. Improvement in valve areas was similar
`with TAVR and surgical replacement and was maintained for 2 years. Paravalvular
`regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular
`regurgitation was associated with increased late mortality (P<0.001).
`
`CONCLUSIONS
`A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative
`to surgery in high-risk patients. The two treatments were similar with respect to
`mortality, reduction in symptoms, and improved valve hemodynamics, but paraval(cid:173)
`vular regurgitation was more frequent after TAVR and was associated with in(cid:173)
`creased late mortality. (Funded by Edwards Lifesciences, Clinica!Trials.gov number,
`NCT00530894.)
`
`1686
`
`N ENGLJ MEO 366;18 NEJM.ORG MAY 3, 2012
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ARIAD PHARMACEUTICALS INC on August 24, 2017. For personal use only. No other uses without permission.
`Copyright© 2012 Massachusetts Medical Society. All rights reserved.
`
`Edwards Lifesciences Corp. v.
`Boston Scientific Scimed
`IPR2017-00060
`US Pat. 8,992,608
`Exhibit 2097
`
`

`

`,,
`
`"
`
`l~!
`
`Tht NEW ENGLAND JOURN1\L oJME.DlC!NE
`
`o_R_1c_11_N_._A_L_f_\_R_T_r_c_L_E_·
`
`~!I
`
`Two-Year Outcomes after Transcatheter
`or Surgical Aortic-Valve Replacement
`Susheel I( Koda!i. M.D., Mathew R. Williams, M.D., Craig R. Smith, M.D.,
`Lars G. Svensson, M.D .. Ph.D.,John G. Webb, M.D., Raj R. Makkar, M.D.,
`Gregory P. Fontana, M.D. Todd M. Dewey, M.D., Vinod H. Thourani, M.D.,
`Augusto D. Pichard, M.D., Michael Fischbein, M.D., Ph.D., Wilson Y Szeto, M.D.,
`Scott Lirn, M.D .. Kevin L. Greason, M.D., Paul S. Teirstein, M.D.,
`S. Chris Malaisrie, M.D., Pamela S. Douglas, M.D., Rebecca T. Hahn. M.D.,
`Brian Whisenant, M.D., Alan Zajarias, M.D., Duolao Wang, Ph.D.,
`JodiJ. Akin, M.S., William N. Anderson, Ph.D., and Martin B. Leon, M.D..
`for the PARTNER Trial Investigators'''
`
`1 J
`
`~
`
`ABSTRACT
`
`\ ~
`
`EXH\B\T J{ (l
`J/0-1~-/7 <fu~ I
`
`From Columbia University Medical Cen(cid:173)
`ter and New York Presbyterian Hospital
`(S.K.K., M.R.W., C.R.S., R.T.H., M.B.L.)
`and Lenox Hill Hospital (G.P.F.) - both
`in New York; Cleveland Clinic Foundation,
`Cleveland (L.G.S.); University of British
`Columbia and St. Paul's Hospital, Vancou(cid:173)
`ver, Canada U.G.W.); Cedars-Sinai Medi(cid:173)
`cal Center, Los Angeles (R.R.M.); Medi(cid:173)
`cal City Dallas, Dallas (T.M.D.); Emory
`University School of Medicine, Atlanta
`(V.H.T.); Washington Hospital Center,
`Washington, DC (A.D.P.); Stanford Uni(cid:173)
`versity Medical School, Palo Alto (M.F.),
`Scripps Clinic, La Jolla (P.S.T.), and Ed(cid:173)
`wards Lifesciences, Irvine U,J.A., W.N.A.)
`- all in California; Hospital of the Uni(cid:173)
`versity of Pennsylvania, Philadelphia
`(W.Y.S.); University of Virginia, Charlottes(cid:173)
`ville (S.L.); Mayo Clinic, Rochester, MN
`(K.L.G.); Northwestern University, Chi(cid:173)
`cago (S.C.M.); Duke University Medical
`Center, Durham, NC (P.S.D.); lntermoun(cid:173)
`tain Medical Center, Salt Lake City (B.W.);
`Washington University Medical School
`and Barnes-Jewish Hospital, St. Louis
`(A.Z.); and London School of Hygiene
`and Tropical Medicine, London (D.W.).
`Address reprint requests to Dr. Kodali at
`Columbia University Medical Center/
`New York Presbyterian Hospital, 161 Fort
`Washington Ave., 6th Fl., New York, NY
`10032, or at sk2427@columbia.edu.
`
`*The investigators, institutions, and re-
`search organizations participating in the
`Placement of Aortic Transcatheter Valves
`(PARTNER) trial are listed in the Supple(cid:173)
`mentary Appendix, available at NEJM.org.
`
`This article (10.1056/NEJMoal200384) was
`published on March 26, 2012, at NEJM.org.
`
`N EnglJ Med 2012;366:1686-95.
`Copyright © 2012 Massachusetts Medical Society.
`
`llACKGl?OUND
`The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among
`high-risk patients with aortic stenosis, the 1-year survival rates are similar with trans(cid:173)
`catheter aortic-valve replacement (TAVR) and surgical replacement. However, longer(cid:173)
`term follow-up is necessary to determine whether TAVR has prolonged benefits.
`
`METHODS
`At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis
`to undergo either surgical aortic-valve replacement or TAVR. All patients were fol(cid:173)
`lowed for at least 2 years, with assessment of clinical outcomes and echocardiographic
`evaluation.
`
`RESULTS
`The rates of death from any cause were similar in the TAVR and surgery groups
`(hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and
`at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the
`surgery group (P=0.78). The frequency of all strokes during follow-up did not differ
`significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23;
`P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical re(cid:173)
`placement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in
`the TAVR group and 12 in the surgery group. Improvement in valve areas was similar
`with TAVR and surgical replacement and was maintained for 2 years. Paravalvular
`regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular
`regurgitation was associated with increased late mortality (P<0.001).
`
`CONCLUSIONS
`A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative
`to surgery in high-risk patients. The two treatments were similar with respect to
`mortality, reduction in symptoms, and improved valve hemodynamics, but paraval(cid:173)
`vular regurgitation was more frequent after TAVR and was associated with in(cid:173)
`creased late mortality. (Funded by Edwards Lifesciences, Clinica!Trials.gov number,
`NCT00530894.)
`
`1686
`
`N ENGLJ MEO 366;18 NEJM.ORG MAY 3, 2012
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ARIAD PHARMACEUTICALS INC on August 24, 2017. For personal use only. No other uses without permission.
`Copyright© 2012 Massachusetts Medical Society. All rights reserved.
`
`

`

`TRANSCATHETER VS. SURGICAL AORTIC-VALVE REPLACEMENT
`
`'t
`
`.. ;i ~- \ high mortality after the appearance of car-
`
`ORTIC STENOSIS IS ASSOCIATED WITH
`
`diac symptoms.1 Nevertheless, many pa(cid:173)
`tients do not undergo surgical aortic-valve replace(cid:173)
`ment owing to real or perceived increased risks
`associated with surgery. 2-5 Trans catheter aortic(cid:173)
`valve replacement (TAVR) has emerged as an al(cid:173)
`ternative therapy in high-risk patients with aortic
`stenosis. 6-10 Observational registries from vari(cid:173)
`ous countries have reported I-monrh and I-year
`outcomes after TAVR,11-14 but there are limited
`long-term follow-up data.15
`The Placement of Aortic Transcatheter Valves
`(PARTNER) trial was a randomized trial compar(cid:173)
`ing TAVR with standard-of-care therapies in high(cid:173)
`risk patients with aortic stenosis. One-year mor(cid:173)
`tality outcomes from PARTNER showed that TAVR
`was superior to standard therapy in patients who
`could not undergo surgery16 and was noninferior
`to surgical replacement in high-risk patients who
`could undergo surgery.17 However, longer-term
`data are required to assess valve durability and
`to monitor late clinical complications, before
`TAVR is used more widely in clinical practice.
`This report describes the 2-year (and longer) clini(cid:173)
`cal outcomes and echocardiographic findings after
`TAVR or surgical aortic-valve replacement in the
`high-risk patients in the PARTNER trial who could
`undergo surgery.
`
`formed through a small intercostal incision over
`the left ventricular apex with the use of a dedicat(cid:173)
`ed delivery catheter and the same SAPIEN valve.
`Heparin was administered during the proce(cid:173)
`dure, and dual antiplatelet therapy (aspirin and
`clopidogrel) was recommended for 6 months af..
`terward. The outpatient regimen was frequently
`modified by the treating physicians because of
`increased bleeding risks.
`
`STUDY DESIGN AND OVERSIGHT
`The study design and data-management practices
`have been described previously.16•17 A total of 699
`patients from 25 sites were randomly assigned to
`TAVR or surgical replacement. Patients assigned
`to TAVR were treated by either the transfemoral or
`transapical approach on the basis of whether pe(cid:173)
`ripheral arteries could accommodate the large
`sheaths required (22 French for the 23-mm valve
`and 24 French for the 26-mm valve). Patients who
`were randomly assigned to surgical replacement
`were stratified according to whether a transferno(cid:173)
`ral or transapical approach would have been used.
`The study was designed and monitored by the
`sponsor, Edwards Lifescierices, and the executive
`committee, which included four interventional
`cardiologists and four cardiac surgeons. The spon(cid:173)
`sor funded the study and participated in the se(cid:173)
`lection and management of the sites, the collec(cid:173)
`tion of the data, and data monitoring. The first
`author and members of the executive committee
`had unrestricted access to the data after the data(cid:173)
`base had been locked and prepared all drafts of
`the manuscript; they attest to the completeness
`and accuracy of the reported data and to the ad(cid:173)
`herence of the study to the protocol (available with
`the full text of this article at NEJM.org). The trial
`was approved by the institutional review board
`at each site. Written informed consent was ob(cid:173)
`tained from all patients.
`
`STUDY END POINTS
`The prespecified primary end point of the PART(cid:173)
`NER trial was all-cause mortality at 1 year for the
`pooled cohort. Prespecified secondary end points
`included cardiovascular mortality, stroke, repeat
`hospitalization, acute kidney injury, vascular com(cid:173)
`plications, bleeding events, and New York Heart
`Association (NYHA) functional class. All patients
`were followed for at least 2 years and had annual
`clinical visits and echocardiographic evaluations.
`Crossovers between the two treatment groups were
`not permitted. A clinical-events committee was
`
`METHODS
`
`PATIENTS
`Patient selection for this cohort of the PARTNER
`trial has been described previously." Inclusion cri(cid:173)
`teria were severe symptomatic aortic stenosis (an
`aortic-valve area 5.0.8 cm2 plus a peak velocity L4 m
`per second or a mean valve gradient L40 mm Hg)
`and high-risk status for surgical aortic-valve re(cid:173)
`placement, as determined by experienced surgeons.
`Patients were considered to be at high surgical
`risk if they had coexisting conditions that were
`associated with a risk of death of at least 15% by
`30 days after the operation.
`
`STUDY DEVICE AND PROCEDURE
`The SAPIEN heart-valve system (Edwards Life(cid:173)
`sciences) and the TAVR procedure have been de(cid:173)
`scribed previously.16•17 Most procedures were per(cid:173)
`formed in a hybrid operating room with a fixed
`fluoroscopic imaging system, while the patient was
`under general anesthesia, and with transesopha(cid:173)
`geal echocardiography. Transapical TAVR was per-
`
`N ENGLJ MED 366;18 NEJM.ORG MAY 3, 2012
`
`1687
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ARJAD PHARMACEUTICALS INC on August 24, 20 I 7. For personal use only. No other uses without permission.
`Copyright© 2012 Massachusetts Medical Society. All rights reserved.
`
`

`

`.,
`
`The NEW ENGL1\ND JOURNAi.. oJMED!ClNE
`
`tory of coronary artery disease, 43.0% had a his(cid:173)
`tory of coronary-artery bypass surgery, 42.4% had
`peripheral vascular disease, 43.3% had pulmo(cid:173)
`nary disease, and 41.3% had diabetes), The TAVR
`and surgery groups were generally well matched
`with regard to baseline characteristics (Table 1
`in the Supplementary Appendix), except for a
`slightly higher incidence of renal dysfunction in
`the TAVR group (creatinine level >2 mg per deci(cid:173)
`liter [177 µ,mo! per liter): 10.8%, as compared
`with 6.4% in the surgery group; P=0.04). The
`mean Society ofThoracic Surgeons predicted risk
`of death at 30 days was 11.8±3.4%.
`Of the 699 study patients, 42 did not receive
`the assigned therapy: 4 in the TAVR group and 38
`in the surgery group.17 The main reasons for non(cid:173)
`treatment were withdrawal from the study and
`the patient's decision not to undergo surgery (28
`patients).
`
`responsible for adjudicating all end points. Defi(cid:173)
`nitions of the end points are identical to those in
`the original trial and have been reported else(cid:173)
`where.16,17
`
`STATISTICAL ANALYSIS
`For data analyses, the intention-to-treat analysis
`started at the time of randomization, and the as(cid:173)
`treated analysis started at the time of induction
`of anesthesia in the procedure room. All clinical
`outcomes were primarily analyzed with the use
`of an intention-to-treat analysis, but the results
`of as-treated analyses are also presented for com(cid:173)
`parison. All echocardiographic analyses were per(cid:173)
`formed with the use of the as-treated data. Cat(cid:173)
`egorical variables were compared with the use of
`Fisher's exact test. Continuous variables, presented
`as means ±SD, were compared with the use of
`Student's t-test. Survival curves for time-to-event
`variables were constructed with the use of Kap(cid:173)
`lan-Meier estimates based on all available data
`and were compared with the use of the log-rank
`test. To study the effect of risk factors on mortal(cid:173)
`ity, Cox proportional-hazards regression was per(cid:173)
`formed. For the multivariable analyses, multiple
`imputations were used to accommodate missing
`baseline variables. The multivariable models in(cid:173)
`cluded covariates with a P value ofless than 0.20
`in univariate analyses. An additional time-depen(cid:173)
`dent covariate analysis was performed to test the
`association of complications during TAVR or sur(cid:173)
`gical replacement with subsequent mortality. All
`statistical analyses were performed with the use
`of SAS software, version 9.2.
`
`MORTALITY AND STROKE
`Outcomes at 30 days and 1 year have been de(cid:173)
`scribed previously.17 For the duration of the trial,
`there were no significant differences in survival
`between the TAVR and surgery groups in either
`the intention-to-treat analysis (hazard ratio with
`TAVR, 0.90; 95% confidence interval [CI], 0.71 to
`1.15; P=0.41) or the as-treated analysis (hazard
`ratio, 0.98; 95% CI, 0.76 to 1.25; P=0.85) (Fig. 1).
`Between 1 and 2 years, there were 32 additional
`deaths in the TAVR group and 25 in the surgery
`group. At 2 years, there were no significant dif..
`ferences in mortality from any cause between the
`TAVR group (33.9%; 95% CI, 28.9 to 39.0) and
`the surgery group (35.0%; 95% CI, 29.8 to 40.2;
`P=0.78) (Table 1). Cardiovascular mortality at
`2 years was also similar in the TAVR and surgery
`groups (21.4% [95% CI, 16.8 to 26.0J and 20.5%
`[95% CI, 15.8 to 25.3), respectively; P=0.80). Sim(cid:173)
`ilarly, in the as-treated analysis, the TAVRand sur(cid:173)
`gery groups did not differ significantly with re(cid:173)
`spect to all-cause mortality (33.9% and 32.7%,
`respectively; P=0.75) or cardiovascular mortality
`(20.8% and 18.5%, respectively; P=0.50) (Table 2
`in the Supplementary Appendix).
`Between 1 and 2 years, eight strokes occurred
`(four in the TAVR group and four in the surgery
`group) and three transient ischemic attacks (two
`in the TAVR group and one in the surgery group).
`The frequency of all neurologic events (strokes and
`transient ischemic attacks) at 2 years was higher
`with TAVR than with surgical replacement (11.2%
`
`RJ;:SULTS
`
`PATIENTS
`In the randomized TAVR group, 244 patients had
`acceptable vascular access and were treated by
`means of the transfemoral approach, and the re(cid:173)
`maining 104 patients were treated by means of
`the transapical approach. Surgical replacement
`was performed in 351 patients. Figure 1 in the
`Supplementary Appendix, available at NEJM.org,
`shows the study-group assignments and follow(cid:173)
`up. All patients were followed for at least 2 years
`(median, 727 days; maximum, 1490 days). The
`overall study population was elderly (mean age,
`84.1±6.6 years), had severe cardiac symptoms
`(94.1% had NYHA class III or IV status), and had
`frequent coexisting conditions (75.5% had a his-
`
`1688
`
`N ENGL) MED 366;18 NEJM.ORG MAY 3, 2012
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ARIAD PHARMACEUTICALS INC on August 24, 2017. For personal use only. No other uses without permission.
`Copyright© 2012 Massachusetts Medical Society. All rights reserved.
`
`

`

`TRANSCATHETER VS. SURGICAL AORTIC-VALVE REPLACEMENT
`
`A Death from Any Cause, Intention-to-Treat Population
`60 Hazard ratio, 0.90 (95% Cl, 0.71-1.15)
`[ 50
`P=0.41
`..
`QI
`"'
`::,
`40
`u
`>,
`,:
`<
`E
`~
`0
`,£
`"'
`QI
`C
`
`30
`
`20
`
`10
`
`B Death from Any Cause, As-Treated Population
`60 Hazard ratio, 0.98 (95% Cl, 0.76-1.25)
`l 50 P-0.85
`QI
`"'
`::,
`"'
`u
`>,
`,:
`<
`E
`~
`0
`...
`..c
`
`40
`
`30
`
`20
`
`10
`
`QI
`C
`
`6
`
`12
`
`18
`Month
`
`24
`
`30
`
`36
`
`6
`
`12
`
`18
`Month
`
`24
`
`30
`
`36
`
`No. at Risk
`TAVR
`Surgery·
`
`348
`351
`
`298
`252
`
`260
`236
`
`234
`217
`
`172
`165
`
`70
`65
`
`31
`32
`
`No. at Risk
`TAVR
`Surgery
`
`344
`313
`
`291
`243
`
`259
`229
`
`232
`211
`
`155
`143
`
`70
`63
`
`29
`28
`
`C Stroke, Intention-to-Treat Population
`60
`
`D Death from Any Cause or Stroke, Intention-to-Treat Population
`60
`
`50
`
`Hazard ratio, 1.22 (95% Cl, 0.67-2.23)
`P=0.52
`
`i 40
`..
`-
`
`.&
`a::
`,:
`QI
`>
`w
`
`30
`
`20
`
`10
`
`r::==
`0
`0
`
`6
`
`12
`
`24
`
`18
`Month
`
`Hazard ratio, 0.93 (95% Cl, 0.73-1.18)
`P~0.55
`
`50
`
`i 40
`-
`.&
`"'
`a::
`,:
`QI
`>
`w
`
`30
`
`20
`
`10
`
`6
`
`12
`
`18
`Month
`
`24
`
`30
`
`36
`
`Surgery
`
`I
`
`30
`
`TAVR
`36
`
`No. at Risk
`TAVR
`Surgery
`
`348
`351
`
`287
`246
`
`249
`230
`
`224
`211
`
`162
`160
`
`65
`62
`
`28
`31
`
`No. at Risk
`TAVR
`Surgery
`
`348
`351
`
`291
`247
`
`254
`232
`
`230
`213
`
`168
`162
`
`68
`63
`
`29
`31
`
`Figure l. Time-to-Event Curves for the Primary and Other Selected End Points.
`Events were calculated with the use of Kaplan-Meier methods and compared with the use of a log-rank test. TAVR denotes transcatheter
`aortic-valve replacement.
`
`vs. 6.5%, P=0.05). However, there was no signifi(cid:173)
`cant difference in the number of overall strokes
`between the TAVR and surgery groups (hazard
`ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52) (Fig. 1).
`After the early increased hazard of stroke in the
`first 30 days associated with TAVR (4.6% with
`TAVR vs. 2.4% with surgical replacement, P=0.12),
`there were 8 additional strokes in the TAVR group
`and 12 in the surgery group, such that the total
`number of strokes over the follow-up period (36
`months) was 24 in the TAVR group and 20 in the
`surgery group. The composite of the rate of death
`from any cause or stroke did not differ signifi(cid:173)
`cantly between the two treatment groups (hazard
`ratio, 0.93; 95% CI, 0.73 to 1.18; P=0.55) (Fig. 1);
`at 2 years, the rate was 37.1% in the TAVR group
`and 36.4% in the surgery group (P=0.85).
`
`OTHER CLINICAL OUTCOMES
`Other clinical events are summarized in Table 1.
`Major vascular complications and major bleeding
`events were frequent procedure-related complica(cid:173)
`tions in the TAVR and surgery groups, respec(cid:173)
`tively, but after 1 year, these events were uncom(cid:173)
`mon and did not differ significantly between the
`groups. No patients were treated with balloon aor(cid:173)
`tic valvuloplasty or repeat TAVR between 1 and
`2 years. Endocarditis was rare. and occurred at a
`similar rate in the two groups (1.5% in the TAVR
`group and 1.0% in the surgery group, P=0.61).
`No patients in either group had structural valve
`deterioration requiring surgical replacement dur(cid:173)
`ing follow-up.
`At 2 years, there was no significant difference
`in the rate of repeat hospitalization between the
`
`N ENGLJ MEO 366;18 NEJM.ORG MAY 3, 2012
`
`1689
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`Copyright© 2012 Massachusetts Medical Society. All rights reserved,
`
`

`

`J'
`
`The N E IV ENG L ,\ N D / 0 U R NA L oJ M ED IC l N E
`
`Table 1. Clinical Outcomes at 1 Year and 2 Years with TAVR or Surgery (Intention-to-Treat Population).*
`
`Outcome
`
`1 Year
`
`2 Years
`
`Death
`From any cause
`From cardiovascular causes
`Repeat hospitalization+
`Death from any cause or repeat
`hospitalization:j:
`Stroke or TIA§
`All
`Stroke
`TIA
`Death from any cause or stroke
`Myocardial infarction
`Major vascular complication,
`Major bleeding]
`Endocarditis
`Renal failure**
`New pacemaker
`SVD requiring surgical replacement
`
`Surgery
`(N=351)
`
`TAVR
`(N-348)
`
`P Value ]
`
`Surgery
`(N-351)
`
`TAVR
`(N =348)
`
`P Value+
`
`no. of patients (%)
`
`no. of patients (%)
`
`89 (26.8)
`40 (13.0)
`51 (17.7)
`125 (37.7)
`
`84 (24.3)
`47 (14.3)
`59 (18.6)
`121 (34.9)
`
`0.45
`0.63
`0.78
`0.45
`
`114 (35.0)
`59 (20.5)
`60 (21.7)
`152 (46.5)
`
`116 (33.9)
`67 (21.4)
`74 (24.7)
`159 (46.6)
`
`0.78
`0.80
`0.41
`0.99
`
`13 (4.3)
`10 (3.2)
`4 (1.5)
`95 (28.6)
`2 (0.6)
`13 (3.8)
`88 (26.7)
`3 (1.0)
`20 (6.5)
`16 (5.0)
`0
`
`28 (8.7)
`20 (6.0)
`8 (2.6)
`95 (27.4)
`0
`39 (11.3)
`52 (15. 7)
`2 (0.6)
`18 (5.4)
`21 (6.4)
`0
`
`0.03
`0.08
`0.32
`0.74
`0.16
`<0.001
`<0.001
`0.63
`0.57
`0.44
`
`18 (6.5)
`14 (4.9)
`5 (2.0)
`119 (36.4)
`4 (1.5)
`13 (3.8)
`95 (29.5)
`3 (1.0)
`21 (6.9)
`19 (6.4)
`0
`
`34 (11.2)
`24 (7.7)
`10 (3.6)
`127 (37.1)
`0
`40 (11.6)
`60 (19.0)
`4 (1.5)
`20 (6.2)
`23 (7.2)
`0
`
`0.05
`0.17
`0.26
`0.85
`0.05
`<0.001
`0.002
`0.61
`0.75
`0.69
`
`* All percentages are Kaplan-Meier estimates at the specific time point and thus do not equal the number of patients
`divided by the total number in the study group. SVD denotes structural valve deterioration, TAVR transcatheter aortic(cid:173)
`valve replacement, and TIA transient ischemic attack.
`t P values are for between-group comparisons of the frequency of the event at each time point.
`:j: Repeat hospitalizations were included in the analysis if they were for symptoms of heart failure, angina, or syncope
`due to aortic-valve disease that required aortic-valve intervention or intensified medical management.
`§ Stroke was defined as a neurologic deficit lasting more than 24 hours or lasting less than 24 hours with a brain-imag(cid:173)
`ing study showing infarction.
`"i Major vascular complications were defined as thoracic aortic dissection; access-site or access-related vascular injury
`leading to death, the need for substantial blood transfusion (>3 units), or percutaneous or surgical intervention; and
`distal embolization (noncerebral) from a vascular source requiring surgery or amputation or resulting in irreversible
`end-organ damage.
`Major bleeding was defined as any episode of major internal or external bleeding that caused death, hospitalization,
`or permanent injury or that necessitated the transfusion of at least 3 units of packed red cells or a pericardiocentesis
`procedure.
`** Renal failure was defined as any condition requiring the initiation of any dialysis.
`
`TAVR and surgery groups (24.7% and 21.7%, re(cid:173)
`spectively; P=0.41). Among survivors at 2 years,
`the mean NYHA class was similar in the TAVR
`and surgery groups (1.72 and 1.70, P=0.87), and
`the majority of patients in both groups had NYHA
`class I or II status (83.9% in the TAVR group and
`85.2% in the surgery group). Clinical outcomes in
`the subgroups of patients in whom a transferno(cid:173)
`ral or transapical approach was used are shown
`in Tables 3 through 6 in the Supplementary Ap(cid:173)
`pendix.
`
`PREDICTORS OF MORTALITY
`Predictors of mortality for the overall trial cohort
`as well as for each of the randomized groups are
`presented in Table 2. Treatment assignment was
`not a significant predictor of the risk of death.
`The time-dependent effect of treatment com(cid:173)
`plications on subsequent mortality was also eval(cid:173)
`uated. Strokes greatly increased the hazard of
`death in both groups (TAVR: hazard ratio, 2.47;
`95% CI, 1.42 to 4.30; P<0.001; surgery: hazard
`ratio, 5.20; 95% CI, 3.07 to 8.80; P<0.001). Major
`
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`
`N ENGLJ MED 366;18 NEJM.ORG MAY 3, 2012
`
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`
`

`

`TRANSCATHETER VS. SURGICAL AORTIC-VALVE REPLACEMENT
`
`Table 2. Multivariable Predictors of Mortality.*
`
`Hazard Ratio
`(95% Cl)
`
`0.89 (0.70-1.13)
`0.96 (0.94-0.98)
`2.24 (1.30-4.00)
`0.89 (0.81-0.98)
`1.04 (1.01-1.08)
`1.36 (1.02-1.82)
`
`0.93 (0.90-0.97)
`0.82 (0.72-0.94)
`1.06 (1.00-1.13)
`1.85 (1.01-3.39)
`
`P Value
`
`0.34
`<0.001
`0.006
`0.02
`0.02
`0.04
`
`<0.001
`0.003
`0.04
`0.05
`
`Variable
`Overall.
`TAVR group
`Body-mass indext
`Liver disease:j:
`Mean gradient per increase oflO mm Hg
`STS risk score§
`Moderate or severe mitral regurgitation at baseline
`TAVR
`Body-mass index+
`Mean gradient per increase oflO mm Hg
`Creatinine level at baseline,
`Prior vascular surgery or stent
`Surgery
`CABG
`STS risk score§
`Liver disease:):
`Moderate or severe mitral regurgitation at baseline
`
`0.002
`0.004
`0.02
`0.006
`* Unless otherwise indicated, the hazard ratio reflects the presence or absence of the variable. CABG denotes coronary(cid:173)
`artery bypass grafting.
`t For body-mass index (the weight in kilograms divided by the square of the height in meters), the hazard ratio reflects
`an increase of 1.
`:): Liver disease indicates a history of any liver condition.
`§ The Society of Thoracic Surgeons (STS) risk score predicts the 30-day risk of death (on a scale of0% to 100%, with
`higher scores indicating higher predicted risk). The hazard ratio reflects an increase of 1%.
`, For creatinine level at baseline, the hazard ratio reflects an increase of 1 mg per deciliter.
`
`0.57 (0.40-0.82)
`1.07 (1.02-1.12)
`2.59 (1.16-5.43)
`1. 77 (1.17-2.68)
`
`bleeding also increased the hazard of death in
`both groups (TAVR: hazard ratio, 2.11; 95% CI,
`1.41 to 3.17; P<0.001; surgery: hazard ratio, 2.94;
`95% CI, 2.08 to 4.15; P<0.001). Major vascular
`complications affected survival only in the TAVR
`group (hazard ratio, 1.71; 95% CI, 1.07 to 2.73;
`P=0.02).
`
`ECHOCARDIOGRAPHIC FINDINGS
`The early hemodynamic improvements that were
`seen with both surgical replacement and TAVR
`were maintained at 2 years, with no significant
`changes in valve areas or mean gradients (Fig. 2).
`Moderate or severe paravalvular aortic regurgita(cid:173)
`tion was more common after TAVR than after
`surgical replacement at both 1 and 2 years (7.0%
`vs. 1.9% at 1 year, and 6.9% vs. 0.9% at 2 years;
`P<0.001 for both comparisons). Among the 143
`patients who underwent echocardiographic eval-
`
`uation 2 years after TAVR, paravalvular aortic re(cid:173)
`gurgitation remained unchanged in 46.2% of pa(cid:173)
`tients, was improved in 31.5%, and was worse in
`22.4% (Table 7 in the Supplementary Appendix).
`The presence of paravalvular or total aortic re(cid:173)
`gurgitation (mild, moderate, or severe vs. none or
`trace) after TAVR was associated with increased
`late mortality (hazard ratio, 2.11; 95% CI, 1.43 to
`3.10; P<0.001) (Fig. 3). The effect of aortic regur(cid:173)
`gitation on mortality was proportional to the se(cid:173)
`verity of the regurgitation (Fig. 3), but even mild
`aortic regurgitation was associated with an in(cid:173)
`creased rate of late deaths.
`
`DISCUSSION
`
`The salient findings from this 2-year analysis of
`the randomized PARTNER trial are as follows:
`mortality after TAVR remained similar to that
`
`N ENGLJ MEO 366;18 NEJM.ORG MAY 3, 2012
`
`1691
`
`The New England Journal of Medicine
`Downloaded from nejm.org at ARIAD PHARMACEUTICALS INC on August 24, 2017. For personal use only. No other uses without permission.
`Copyright© 2012 Massachusetts Medical Society. All rights reserved.
`
`

`

`The NEW ENGL,\ND JOl.lRNi\l.. oJ;\IED!CINE
`
`..
`
`A
`
`8
`
`2.5
`
`2.0
`
`LS
`
`LO
`
`0.5
`
`o.o
`
`No. at Risk
`Surgery
`TAVR
`
`..
`J:
`- C:
`E
`_g_
`.,
`'o
`I! o
`.. .,
`
`C:
`
`:i
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`a
`
`--- TAVR
`
`·• '- Surgery
`
`P-0.54
`
`r
`, -- -~--l_j
`1
`;/ :~~-001
`
`P=0.002
`
`P=0.003
`
`P-~.16
`
`T
`l
`P-0.32
`
`·-··- ·--. ··-·· ··-··. ·-·-·-·-·---· -·--···--··-1
`P=0.53
`
`Baseline
`
`30 Day
`
`6 Mo
`
`l Yr
`
`2 Yr
`
`224
`290
`110
`151
`163
`301
`269
`139
`210
`223
`---------·-·--·-------------
`
`r
`
`r----· .. -----
`P-0.01
`
`P=0.22
`
`i
`
`L
`30 Day
`
`Baseline
`
`P=0.08
`
`P=0.005
`
`P=0.16
`
`6 Mo
`
`l Yr
`
`2 Yr
`
`niques, and device technologies.12,14,16-18 How(c