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Electronic letters published:
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Is the NNTb quoted a point estimate or one end point of CI
Reply to letters
Cardiac Resynchronization in Patients with Symptomatic Heart Failure
Cardiac resynchronization therapy in heart failure
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Ian TF Cheung, MBChB, FRCSEd Hospital Authority HKSAR
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cheungtf{at}ha.org.hk Ian TF Cheung
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We have tried to use the software CMA to simulate the meta-analysis, and our result for all-cause mortality revealed : NNT 62.5 and (95%CI: NNTB 26.3 to ¡Û to NNTH 200). Could you share with us your method to arrive at the number needed to treat for benefit (NNTB) of 24 in the context of all-cause mortality? What is the baseline risk used for calculation? Is the NNT B a point estimate or just an end point of CI? Thank you for your valuable advice. Conflict of Interest:None declared |
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Finlay A. McAlister, MD MSc FRCPC University of Alberta, Natasha Wiebe, William Abraham
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Finlay.McAlister{at}ualberta.ca Finlay A. McAlister, et al.
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We thank Drs. Calvert, Freemantle, Cleland, and Carbajal for their interest in our paper. We agree with Dr. Carbajal that several trials included in our systematic review had potential methodologic deficiencies and although we only had space to highlight one in our published manuscript (randomization after implantation of the CRT device in all but one trial), we refer interested readers to our full AHRQ report (http://www.ahrq.gov/clinic/epcix.htm) for a full description of the methodology and quality assessment tables for all of the studies included in both our efficacy and safety analyses. We refute the allegation of Drs. Calvert and colleagues that our analysis of the COMPANION[1] data “ignored a basic tenet of meta-analysis” – as outlined in our manuscript, we did conduct intention-to-treat analyses for all endpoints and halfing the control group data when incorporating a three-arm trial in a meta-analysis is one of the techniques endorsed by the Cochrane Collaboration (see http://www.cochrane -net.org/openlearning/HTML/modA2-5.htm). Indeed, we would like to point out that, despite their assertion that “through artefact” we “created statistically significant decreases” for the CRT alone arm of COMPANION, careful perusal of our figure 2 reveals that the RR we reported for mortality in the COMPANION CRT alone arm (0.84, 95% CI 0.61-1.14) is not statistically significant and is in fact very similar to the 0.85 (95% CI 0.67-1.09) they found in their analysis. On the other hand, Drs. Calvert and colleagues are correct in pointing out (as did Dr. Hlatky in the editorial accompanying our paper) that exclusion of the CRT-ICD arm of COMPANION would change the pooled mortality RR with CRT to 0.84 (95% CI 0.69-1.03). We do not disagree that this is one way to approach the data, but we wonder to what extent this argument is moot in light of the current ICD evidence base, particularly given the data from SCD-HeFT.[2,3] Shouldn’t patients with (i) substantial heart failure symptoms despite medical therapy, (ii) prolonged QRS duration, and (iii) LVEF < 35% (the base case in our systematic review and the subsequent decision analysis) be considered for an ICD unless there are contraindications or competing comorbidities? Indeed, we believe that the vast majority of patients with NYHA class III symptomatology who are being evaluated for CRT will also be eligible for an ICD. Given this, isn’t the data from the CRT-ICD arm of COMPANION relevant to the discussion? Further, it should be emphasized that the beneficial effects of CRT on functional status, LVEF, and quality of life which we reported are present even without inclusion of the COMPANION CRT- ICD data. Dr. Calvert and colleagues state that the heart failure hospitalization data is inconclusive. Certainly, the pooled estimate which we reported in the manuscript and which they reiterate in their letter is inconclusive. However, in re-examining our data to formulate a response to these letters and ACP Journal Club, we have discovered an error in the published manuscript. We mistyped the number of “no deaths” in the CRT group for CONTAK-CD[4] when entering the data into our models - a corrected figure 3 is attached. The corrected pooled RR for heart failure hospitalizations is thus 0.67 (95% CI 0.48-0.92)- a result which is statistically and clinically significant and does not include the COMPANION results (the data for this endpoint was not available at the time of our request to the COMPANION investigators). While we disagree with the specific points raised in the first half of their letter by Dr. Calvert and colleagues, we do not disagree with their latter point that these trials may have overestimated the benefits of CRT. Indeed, we made this very point in our manuscript. We also agree with these CARE-HF Investigators that our meta-analysis (which is based on only 429 deaths and 251 heart failure hospitalizations) should not be used as a reason to prematurely terminate ongoing large trials in this area (such as CARE-HF and RAFT). In closing, we would like to reiterate 3 key points which we made in our original manuscript but which we fear may have been missed by some readers: (1) CRT is not a panacea, (2) CRT is efficacious in selected patients with advanced systolic heart failure and evidence of electromechanical dys-synchrony, and (3) attempts to define which patients are most likely to benefit from CRT should remain a research priority. Sincerely, Finlay A. McAlister Natasha Wiebe William Abraham REFERENCES: 1. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. for the COMPANION Investigators. Effect of cardiac resynchronization therapy with and without an implantable defibrillator on morbidity and mortality in advanced chronic heart failure: The COMPANION Trial. N Engl J Med 2004;350:2140-50. 2. Ezekowitz J, Armstrong PW, McAlister FA. Implantable cardioverter defibrillators in primary and secondary prevention: a systematic review of randomized, controlled trials. Ann Intern Med 2003;138:445-452. 3. Cleland JGF, Ghosh J, Freemantle N, Kaye GC, Nasir M, Clark AL, et al. Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS- US, RIO-LIPIDS and cardiac resynchronization therapy in heart failure. Eur J Heart Failure 2004;6:501-8. 4. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42:1454-9. CORRECTED FIGURE 3: Heart failure hospitalizations with cardiac resynchronization therapy (CRT) versus controls. Conflict of Interest:Same as listed in original manuscript. |
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Melanie J. Calvert, PhD University of Birmingham, Nick Freemantle, and John G.F. Cleland
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M.Calvert{at}bham.ac.uk Melanie J. Calvert, et al.
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To the editor: McAlister et al. conclude from their meta-analysis that in selected patients with heart failure, cardiac resynchronization therapy improves functional and hemodynamic staus, reduces heart failure hospitalizations, and reduces all-cause mortality1. Such conclusions are however unsafe and are based on an incorrect presentation of the existing scientific data. A major problem with this analysis is that potential differences in the efficacy of CRT delivered with or without an ICD are not dealt with appropriately. Of particular concern, is the way that the all-cause mortality data from the COMPANION trial are presented which fails to preserve randomisation, ignoring a basic tenet of meta-analysis2;3. Incorrectly the authors split the control arm results into two and compare half to the results from CRT alone and the remaining half to results from the CRT+ICD arm. Through this artefact, the authors create statistically significant decreases in all-cause mortality for both active treatment groups. If, however, an appropriate and unconfounded analysis is conducted, comparing only the CRT alone group versus the control group (n=308), preserving randomisation, we observe a non-significant reduction in mortality attributable to CRT (RR 0.85 95%CI 0.67 to 1.09). Indeed, it is the inappropriate inclusion of the CRT+ICD data from this study that led to the appearance of overall statistically significant pooled reduction in all-cause mortality. Removal of this confounded data leads to a non-significant pooled decrease in the relative risk of all-cause mortality (RR 0.84, 95% CI 0.69 to 1.03). Clearly there remain important questions on the impact of CRT on mortality and the additional impact of CRT + ICD. Secondly, their analysis of heart failure hospitalisations is inconclusive. Their pooled data provide an estimate of the relative risk of hospitalisation of 0.68 with a 95% CI of 0.41 to 1.12. This result was based on only 316 events from proof-of-concept studies designed to assess whether cardiac resynchronization could improve symptoms, ventricular function, and exercise capacity. Whilst this result was non-significant the authors then perform a subgroup analysis on which they base their conclusion that in selected patients CRT reduces heart failure hospitalisations. The authors fail to include results from the large COMPANION trial in their analysis, presumably since heart failure hospitalization was reported as part of a composite outcome combined with death from heart failure2. It is unfortunate that the authors were unable to include results from this large study. Finally, the authors acknowledge that these trials probably overestimate the potential benefits of CRT. Only patients with a successful device implant and who survived a run-in period were eligible for randomisation in all but one trial. Moreover, two patients died within hours of crossing over to CRT in the MUSTIC trial4. For all these reasons, the encouraging trends observed in meta-analyses presented so far are not secure evidence of benefit on morbidity or mortality. The double- blind MIRACLE and MIRACLE-ICD trials do suggest that CRT improves symptoms in about 35% and 15% of patients respectively, compared to the control group5;6. However, further manipulation of pharmacological therapy might have achieved similar results. At least two other large controlled trials, with over 1200 patients, have yet to report7;8. Whilst this meta-analysis aims to address an important question, the efficacy and safety of CRT, it fails to provide substantive evidence on the impact of this therapy on mortality and hospitalisation due to heart failure. Melanie Calvert, PhD, Nick Freemantle, PhD Primary Care and General Practice University of Birmingham Medical School Edgbaston, England John G. F. Cleland, MD Department of Cardiology University of Hull Kingston upon Hull, England References 1. McAlister FA, Ezekowitz JA, Wiebe N, Rowe B, Spooner C, Crumley E et al. Systematic Review: Cardiac Resynchronization in Patients with Symptomatic Heart Failure. Ann Intern Med 2004;141:381-90. 2. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T et al. Cardiac-Resynchronization Therapy with or without an Implantable Defibrillator in Advanced Chronic Heart Failure. N Engl J Med 2004;350:2140-50. 3. Egger M, Davey Smith G, Altman D. Systematic Reviews in Health Care: Meta-analysis in Context. BMJ Publishing Group, London, 2001. 4. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C et al. Effects of Multisite Biventricular Pacing in Patients with Heart Failure and Intraventricular Conduction Delay. N Engl J Med 2001;344:873. 5. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E et al. Cardiac Resynchronization in Chronic Heart Failure. N Engl J Med 2002;346:1845. 6. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B et al. Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure: The MIRACLE ICD Trial. JAMA 2003;289:2685-94. 7. Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points. European Journal of Heart Failure 2001;3:481-9. 8. Leclercq C,.Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. Journal of the American College of Cardiology 2002;39:194-201. Conflict of Interest:Nick Freemantle and John Cleland are steering committee members for the CARE-HF trial. Nick Freemantle and Melanie Calvert are responsible for the analysis of the CARE-HF trial. |
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Enrique V. Carbajal, M.D. VACCHCS, Grace W. Huang, Billy Hu
Send rapid response to journal:
enrique.carbajal{at}med.va.gov Enrique V. Carbajal, et al.
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McAlister and colleagues (1) performed a systematic review concluding that, in selected patients with heart failure, cardiac resynchronization therapy (CRT), when added to medical therapy, reduces all-cause mortality and heart failure hospitalizations. There appears to be a perception among some cardiologists from different geographical areas in the United States that patients with heart failure should receive a device with defibrillator ability and bi- ventricular pacing function. It is likely that the report by McAlister et al (1) will further contribute to this perception and possibly influence practice trends. This systematic review used a comprehensive search strategy as well as intensive extraction and evaluation of data from pertinent publications. However, certain aspects not inherent to the review need to be addressed. This analysis cannot overcome certain methodological deficiencies (e.g., concealed randomization, lack of- or partly-masking, intention to treat analyses) that affected several studies used in this systematic review. Such deficiencies could lead to preferential management or treatment resulting in better or improved outcomes favoring the intervention(s) of interest (e.g., CRT). In addition, the crossover design of several studies further restricts the already limited data available for evaluation of mortality rates and for evaluation of hospitalizations. Of the parallel studies [MIRACLE (3), MIRACLE-ICD (4), COMPANION (5)] noted on figures 2 and 3, only two [MIRACLE (3) and MIRACLE-ICD (4)] described methodology of strong quality. Without these methodological deficiencies, the MIRACLE (3) and MIRACLE-ICD (4) trials revealed small and statistically not significant differences in mortality rates between patients randomized to CRT compared to inactive-device (no-CRT) therapy. Interestingly, subgroup analyses in the COMPANION (5) trial suggested a beneficial effect of CRT-defibrillator therapy on death rates, compared to pharmacologic therapy, if patients were taking an ACE-inhibitor, a beta -blocker, or spironolactone. This beneficial effect was not seen in patients who were not taking these drugs. In summary, the superb effort exhibited by the authors in this systematic review might be undermined by the weak quality of several studies used for the various analyses. The conclusions from these analyses regarding the use of CRT in patients with symptomatic heart failure should be assessed and confirmed in large trials without methodological deficiencies. Conflict of Interest:None declared |
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