Letters

Table 2. Reporting of Subgroup Analyses in Trial Reports No. (%) of Reports With Subgroup Analyses

Subgroup variables, median (IQR)a

All (n = 46)

Primary (n = 5)

Follow-up (n = 13)

Subgroup (n = 28) 1 (1-1)

NA

2 (1-5)

3 (1-7)

Complexity of coronary disease

NA

3 (60)

8 (62)

5 (18)

Diabetes

NA

2 (40)

13 (100)

11 (39)

Sex

NA

2 (40)

5 (38)

3 (11)

Angina grade

NA

2 (40)

5 (38)

0

Age

NA

1 (20)

5 (38)

3 (11)

Left ventricular function

NA

1 (20)

4 (31)

2 (7)

Proximal LAD artery lesion

NA

1 (20)

5 (38)

2 (7)

Yes

9 (20)

2 (40)

2 (15)

5 (18)

Yes, but for only part of the analyses

8 (17)

1 (20)

4 (31)

3 (11)

29 (63)

2 (40)

7 (54)

20 (71)

Yes

32 (70)

5 (100)

8 (62)

19 (68)

No

14 (30)

0

5 (38)

9 (32)

28 (100)

Interaction test reported

No Subgroup difference claimed

Emphasis on subgroup results Yes

40 (87)

3 (60)

9 (69)

No

6 (13)

2 (40)

4 (31)

Yes

10 (22)

1 (20)

2 (15)

7 (25)

No

36 (78)

4 (80)

11 (85)

21 (75)

0

Advised caution with interpretation or reported as hypothesis-generating

and minimize treatment errors, improving analysis and interpretation of subgroup data should receive more attention. The limitations of this study include the sample size and potential lack of generalizability because of its focus on PCI vs CABG trials. Stuart J. Head, PhD Sanjay Kaul, MD Jan G. P. Tijssen, PhD Patrick W. Serruys, MD, PhD A. Pieter Kappetein, MD, PhD

a

Does not add up to the number of reports in each category because analysis of multiple subgroups within a single report is possible. Other variables on which subgroup analyses were based that were not included in the table because performed infrequently, were analyses according to acute coronary syndrome, reoperation, body mass index, peripheral vascular disease, hypertension, hypercholesterolemia, stent use, type of lesion, smoking, electrocardiogram abnormalities, congestive heart failure, metabolic syndrome, renal disease, occluded vessel, and completeness of revascularization.

ing as a consultant to Novo Nordisk, sanofi, and Boehringer Ingelheim; and owning stock in Johnson & Johnson. No other disclosures were reported. Additional Contributions: We thank the following colleagues for carefully reading the manuscript and providing valuable comments: David R. Holmes Jr, MD (Mayo Clinic, Rochester, Minnesota); Michael J. Mack, MD, and David L. Brown, MD (Baylor Health Care System, Dallas, Texas); and Ad J. Bogers, MD, PhD (Erasmus University Medical Center, Rotterdam, the Netherlands). We further thank Esther M. Stoop, MD (Erasmus University Medical Center, Rotterdam, the Netherlands), for help with the literature searches and study identification. None of these persons received compensation for their work. 1. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet. 2000;355(9209):1064-1069. 2. Sun X, Briel M, Busse JW, et al. Credibility of claims of subgroup effects in randomised controlled trials: systematic review. BMJ. 2012;344:e1553.

Author Affiliations: Department of Cardio-Thoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands (Head, Kappetein); Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California (Kaul); Department of Cardiology, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands (Tijssen); Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands (Serruys). Corresponding Author: A. Pieter Kappetein, MD, PhD, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands ([email protected]). Author Contributions: Drs Head and Kappetein had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kaul, Tijssen, Kappetein. Acquisition of data: Head. Analysis and interpretation of data: Head, Kaul, Tijssen, Serruys, Kappetein. Drafting of the manuscript: Head, Kaul, Kappetein. Critical revision of the manuscript for important intellectual content: Kaul, Tijssen, Serruys, Kappetein. Statistical analysis: Head, Kaul, Tijssen, Kappetein. Study supervision: Serruys, Kappetein. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kaul reported serv2098

Abbreviations: IQR, interquartile range; LAD, left anterior descending; NA, not applicable.

3. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine—reporting of subgroup analyses in clinical trials. N Engl J Med. 2007;357(21):2189-2194. 4. Kolh P, Wijns W, Danchin N, et al; Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI). Guidelines on myocardial revascularization. Eur J Cardiothorac Surg. 2010;38(suppl):S1-S52. 5. Pocock S, Calvo G, Marrugat J, et al. International differences in treatment effect: do they really exist and why? Eur Heart J. 2013;34(24):1846-1852. 6. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332.

COMMENT & RESPONSE

Surgery vs Watchful Waiting for Mitral Regurgitation To the Editor Dr Suri and colleagues1 reported data on 1021 patients with flail mitral valve regurgitation and no or mild symptoms and compared outcomes of surgery within 3 months vs

JAMA November 20, 2013 Volume 310, Number 19

Copyright 2013 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Nanyang Technological University User on 05/24/2015

jama.com

Letters

a watchful waiting strategy. They concluded that early surgery was associated with greater long-term survival and a lower risk of heart failure than initial medical management. We wish to point out several limitations to the study. First, the study was not randomized. Second, patients were assigned to watchful waiting based on the judgment of their cardiologist and not on the triggers defined in the guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA).2 Third, 32.5% of patients had mild symptoms but were not referred for surgery despite this being a class I indication in the ACC/AHA guidelines.2 Fourth, one-third of the patients in the medical therapy group developed heart failure, suggesting patients were not as closely monitored as in the study by Rosenhek et al,3 in which patients were referred for surgery as soon as they developed mild symptoms or left ventricular dysfunction. Fifth, no data were provided about the durability of mitral valve repair or recurrence of mitral regurgitation, which can be as high as 35% at 10 years at leading centers.4 In addition, the study has limited application to mitral valve repair surgery in the United States because 44% of patients who undergo mitral valve surgery have replacement rather than repair,5 in contrast to 7% of patients in the study by Suri et al.1 The consequences of mitral valve replacement can be serious. With bioprosthetic mitral valve replacement, there is a considerable valve failure rate after a decade and with mechanical valves, the 10-year patient survival rate is significantly reduced. The ACC/AHA Task Force developed comprehensive, wellreasoned guidelines based on the best available evidence for the timing of mitral valve surgery in patients with severe mitral regurgitation. A prospective clinical study3 validated the benefits and safety of these guidelines, which have clearly defined indicators for the timing of surgical intervention in patients with severe mitral regurgitation. Suri et al1 did not follow the ACC/AHA guidelines. Thus, this study provides no new data to support prophylactic mitral valve surgery before the onset of symptoms, signs of left ventricular impairment, or the development of atrial fibrillation or pulmonary hypertension. Leandro Slipczuk, MD, PhD Roy Beigel, MD Robert J. Siegel, MD Author Affiliations: Cedars-Sinai Heart Institute, Los Angeles, California. Corresponding Author: Robert J. Siegel, MD, Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA 90048 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Suri RM, Vanoverschelde JL, Grigioni F, et al. Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets. JAMA. 2013;310(6):609-616. 2. Bonow RO, Carabello BA, Chatterjee K, et al; 2006 Writing Committee Members; American College of Cardiology/American Heart Association Task Force. 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(15):e523-e661. 3. Rosenhek R, Rader F, Klaar U, et al. Outcome of watchful waiting in asymptomatic severe mitral regurgitation. Circulation. 2006;113(18):22382244. 4. Flameng W, Meuris B, Herijgers P, Herregods MC. Durability of mitral valve repair in Barlow disease versus fibroelastic deficiency. J Thorac Cardiovasc Surg. 2008;135(2):274-282. 5. Gammie JS, Sheng S, Griffith BP, et al. Trends in mitral valve surgery in the United States: results from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Ann Thorac Surg. 2009;87(5):1431-1439.

To the Editor After analyzing outcomes from registry patients with flail mitral valve leaflets and mitral regurgitation, Dr Suri and colleagues1 suggested that early surgery has an advantage over watchful waiting. This observation adds documentation to debates over the proper treatment.2,3 However, it is not clear whether the apparent benefit suggested for the early surgery group is due to later surgery or absence of surgery in the watchful waiting group. It would be also helpful to know whether the demographics of the late surgery vs no surgery groups might explain the choices made. Remaining unanswered is the extent to which propensity scoring and inverse probability weighting were helpful in elucidating the benefit of treatment in 2 observational study groups that were so different. For example, the early surgery group was 5 years younger and had larger mean left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left atrial diameter, and more class II indications than the watchful waiting group. Bias may occur when apparent differences between 2 groups are characteristics that affected whether or not a patient received surgery instead of due to the effect of the surgery per se.4 Larry A. Weinrauch, MD Author Affiliation: Harvard Medical School, Boston, Massachusetts. Corresponding Author: Larry A. Weinrauch, MD, Harvard Medical School, 521 Mount Auburn St, Ste 204, Watertown, MA 02472 ([email protected] .edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being employed by Blue Cross and Blue Shield of Massachusetts; having provided expert testimony on multiple occasions; and having provided adjudication of cardiovascular events for international trials. 1. Suri RM, Vanoverschelde J-L, Grigioni F, et al. Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets. JAMA. 2013;310(6):609-616. 2. Enriquez-Sarano M, Sundt TM III. Early surgery is recommended for mitral regurgitation. Circulation. 2010;121(6):804-812. 3. Gillam LD, Schwartz A. Primum non nocere: the case for watchful waiting in asymptomatic “severe” degenerative mitral regurgitation. Circulation. 2010;121(6):813-821. 4. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70(1):41-55.

In Reply Dr Slipczuk and colleagues fail to appreciate several important corollaries of the evidence presented in our study detailing the benefits of early surgery in patients with mitral regurgitation due to flail leaflets. First, in the absence of published randomized trials, comparative effectiveness research

jama.com

JAMA November 20, 2013 Volume 310, Number 19

Copyright 2013 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Nanyang Technological University User on 05/24/2015

2099

Letters

remains a national priority for comparing contemporary therapeutic modalities.1 The analyses of our large study population, both overall and in all subsets, using unmatched and matched comparisons, demonstrated that early surgery was associated with better survival and less heart failure than watchful waiting. Second, in the absence of class I triggers for surgery, international guidelines defer to physician judgment (class IIa/b) when near-equipoise exists.1 Whether class II indications were present or not, early surgery was associated with superior outcomes compared with watchful waiting, rendering the discussion of guideline-based triggers irrelevant. Third, current heart valve guidelines were indeed accounted for as patients with heart failure symptoms were excluded from our study. Early surgery was reproducibly associated with improved outcomes in the presence or absence of minor (nonheart failure) symptoms. Fourth, there is no evidence that any intensity of followup, whether close or otherwise, diminishes heart failure risk. Conversely, suppressing mitral regurgitation by early surgery prevents this detrimental outcome.2 Awaiting heart failure symptoms3 or mild left ventricular dysfunction4 prior to surgical correction is associated with a poor prognosis. Fifth, contemporary repair has a low reoperation risk of 0.5% to 1% per year.5 In addition, we disagree that the study has limited applicability to mitral valve surgery in the United States. The most recent data from the Society of Thoracic Surgeons indicate that the national mitral valve repair rate was 69% in 2007 and is increasing.6 However, current guidelines suggest that asymptomatic patients with complex disease should be treated at referral centers, which have higher repair rates (>90%), as in our study. In response to Dr Weinrauch, we are cognizant that a limitation of any retrospective analysis is that of embedded biases. However, it is reassuring that the magnitude of differences in survival and heart failure were striking and consistent using multiple analytic methods. Even though we excluded patients considered inoperable, the early surgery group was paradoxically more severely affected (enlarged left heart dimensions or class II triggers), suggesting more advanced disease. A bias may actually be claimed against early surgery, which nonetheless was lifesaving and decreased heart failure many years following intervention. We cannot formally analyze the causes of deleterious outcomes with watchful waiting. In the initial medical management group, two-thirds of deaths occurred while awaiting surgery. Delayed surgery, while less often repair, was not associated with excessive perioperative risk, but previous studies have shown poor long-term postoperative outcome while awaiting class I triggers.3,4 In summary, contemporary evidence indicates that watchful waiting in anticipation of surgical triggers, even though presented as benign by some, eventually necessitates the performance of rescue surgery while increasing late mortality and heart failure risks.3,4 In contrast, these deleterious consequences may by avoided by performing early surgical correction, which was achieved with low risk and a high repair rate at all study sites in our report. 2100

Rakesh M. Suri, MD, DPhil Maurice Enriquez-Sarano, MD Author Affiliations: Mayo Clinic College of Medicine, Rochester, Minnesota. Corresponding Author: Rakesh M. Suri, MD, DPhil, Mayo Clinic Division of Cardiovascular Surgery, 200 First St SW, Rochester, MN 55905 (suri.rakesh @mayo.edu). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Suri reported receiving grants from Edwards Life Sciences, the Sorin Group, and St Jude Medical; receiving support for travel from the Sorin Group; and serving on the eligibility committee for the Abbott COAPT trial. Dr Enriquez-Sarano reported serving as a board member for Valtech and receiving grant funding from Abbott Vascular. 1. Hlatky MA, Douglas PS, Cook NL, et al. Future directions for cardiovascular disease comparative effectiveness research: report of a workshop sponsored by the National Heart, Lung, and Blood Institute. J Am Coll Cardiol. 2012;60(7):569-580. 2. Montant P, Chenot F, Robert A, et al. Long-term survival in asymptomatic patients with severe degenerative mitral regurgitation: a propensity score-based comparison between an early surgical strategy and a conservative treatment approach. J Thorac Cardiovasc Surg. 2009;138(6):1339-1348. 3. Tribouilloy CM, Enriquez-Sarano M, Schaff HV, et al. Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications. Circulation. 1999;99(3):400-405. 4. Enriquez-Sarano M, Tajik AJ, Schaff HV, Orszulak TA, Bailey KR, Frye RL. Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation. 1994;90(2):830-837. 5. Suri RM, Schaff HV, Dearani JA, et al. Survival advantage and improved durability of mitral repair for leaflet prolapse subsets in the current era. Ann Thorac Surg. 2006;82(3):819-826. 6. Gammie JS, Sheng S, Griffith BP, et al. Trends in mitral valve surgery in the United States: results from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Ann Thorac Surg. 2009;87(5):1431-1439.

Autism in Children Born After In Vitro Fertilization To the Editor Mr Sandin and colleagues1 studied the risk of autism among offspring born after in vitro fertilization (IVF) with a population-based prospective cohort study design using data from the Swedish national health registers. The authors focused on the narrow diagnosis of infantile and childhood autism (autistic disorder) and did not include other forms of autism spectrum disorders (ASDs). With accumulating evidence, autism is now recognized as a single spectrum disorder that represents a family of dimensional phenotypes. The single diagnosis of ASD has been adopted in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5).2 Infantile autism was the only autism diagnosis in the International Classification of Diseases (ICD) when its ninth update was first published in 1977. However, more diagnosis codes (atypical autism, Asperger syndrome, other pervasive developmental disorders, pervasive developmental disorder unspecified) are available in the tenth revision of the ICD and such data should have been captured in the Swedish national patient register. Given current knowledge about autism and the largely unknown pathogenesis that has contributed to the increasing prevalence of ASDs in the past 2 decades,3 it would be informative if the authors could analyze the association between IVF and a broader diagnosis of ASD. Of the more than 2.5 million infants born in this study cohort, 6959 were diagnosed

JAMA November 20, 2013 Volume 310, Number 19

Copyright 2013 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Nanyang Technological University User on 05/24/2015

jama.com

Surgery vs watchful waiting for mitral regurgitation.

Surgery vs watchful waiting for mitral regurgitation. - PDF Download Free
77KB Sizes 0 Downloads 0 Views