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Meta-analysis: Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema

Cui-Lian Weng, MD; Yun-Tao Zhao, PhD; Qing-Hua Liu, MM; Chang-Jun Fu, PhD; Feng Sun, PhD; Yan-Liang Ma, MD; Yan-Wen Chen, MD; and Quan-Ying He, MD
[+] Article and Author Information

From Peking University People's Hospital, Peking University, Beijing Chaoyang Hospital Affiliate of Capital Medical University, and Tsinghua University, Beijing, China, and First Affiliated Hospital of Xiamen University, Xiamen, China.


Note: Drs. Zhao and Weng contributed equally to this manuscript as first authors. Drs. Zhao, Weng, and He are equal corresponding authors.

Acknowledgment: The authors thank Dr. Qing-Fu Liu (National University of Defense Technology) for his outstanding work in the field of hierarchical Bayesian modeling applied in this manuscript.

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M08-2786.

Corresponding Authors: Cui-Lian Weng, MD, and Quan-Ying He, MD, Peking University People's Hospital, 11 Xizhimen South Street, Beijing 100044, China; Yun-Tao Zhao, PhD, Beijing Chaoyang Hospital, Affiliate of Capital Medical University, 8 Baijiazhuang Road, Beijing 100020, China; e-mail, raas@hsc.pku.edu.cn.

Current Author Addresses: Drs. Weng, Ma, Chen, and He: Peking University People's Hospital, 11 Xizhimen South Street, Beijing 100044, China.

Dr. Zhao: Beijing Chaoyang Hospital, Affiliate of Capital Medical University, 8 Baijiazhuang Road, Beijing 100020, China.

Ms. Liu: Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Xiamen University, 55 Zhenghai Road, Xiamen 361003, China.

Dr. Fu: Automation Department, Tsinghua University, Beijing 100084, China.

Dr. Sun: Peking University, 38 Xueyuan Road, Beijing 100191, China.

Author Contributions: Conception and design: C.L. Weng, Y.T. Zhao.

Analysis and interpretation of the data: C.L. Weng, Y.T. Zhao.

Drafting of the article: C.L. Weng, Y.T. Zhao.

Critical revision of the article for important intellectual content: C.L. Weng, Y.T. Zhao.

Final approval of the article: C.L. Weng, Y.T. Zhao, Q.Y. He.

Statistical expertise: Q.H. Liu, C.J. Fu, F. Sun.

Administrative, technical, or logistic support: C.L. Weng, Y.T. Zhao, Y.L. Ma, Y.W. Chen.

Collection and assembly of data: Q.H. Liu.


Ann Intern Med. 2010;152(9):590-600. doi:10.7326/0003-4819-152-9-201005040-00009
Text Size: A A A

This article has been corrected. For original version, click “Original Version (PDF)” in column 2.

Background: Noninvasive ventilation (NIV) is commonly used to treat patients with acute cardiogenic pulmonary edema (ACPE), but the findings of a recent large clinical trial suggest that NIV may be less effective for ACPE than previously thought.

Purpose: To provide an estimate of the effect of NIV on clinical outcomes in patients with ACPE that incorporates recent trial evidence and explore ways to interpret that evidence in the context of preceding evidence that favors NIV.

Data Sources: PubMed and EMBASE from 1966 to December 2009, Cochrane Central Register of Controlled Trials and conference proceedings through December 2009, and reference lists, without language restriction.

Study Selection: Randomized trials that compared continuous positive airway pressure and bilevel ventilation with standard therapy or each other.

Data Extraction: Two independent reviewers extracted data. Outcomes examined were mortality, intubation rate, and incidence of new myocardial infarction (MI).

Data Synthesis: Compared with standard therapy, continuous positive airway pressure reduced mortality (relative risk [RR], 0.64 [95% CI, 0.44 to 0.92]) and need for intubation (RR, 0.44 [CI, 0.32 to 0.60]) but not incidence of new MI (RR, 1.07 [CI, 0.84 to 1.37]). The effect was more prominent in trials in which myocardial ischemia or infarction caused ACPE in higher proportions of patients (RR, 0.92 [CI, 0.76 to 1.10] when 10% of patients had ischemia or MI vs. 0.43 [CI, 0.17 to 1.07] when 50% had ischemia or MI). Bilevel ventilation reduced the need for intubation (RR, 0.54 [CI, 0.33 to 0.86]) but did not reduce mortality or new MI. No differences were detected between continuous positive airway pressure and bilevel ventilation on any clinical outcomes for which they were directly compared.

Limitations: The quality of the evidence base was limited. Definitions, cause, and severity of ACPE differed among the trials, as did patient characteristics and clinical settings.

Conclusion: Although a recent large trial contradicts results from previous studies, the evidence in aggregate still supports the use of NIV for patients with ACPE. Continuous positive airway pressure reduces mortality more in patients with ACPE secondary to acute myocardial ischemia or infarction.

Primary Funding Source: None.

Figures

Grahic Jump Location
Figure 1.
Forest plot for in-hospital mortality.

CPAP = continuous positive airway pressure; RR = relative risk.

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Figure 2.
Forest plot for need for intubation.

CPAP = continuous positive airway pressure; RR = relative risk.

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Figure 3.
Forest plot for incidence of new myocardial infarction.

CPAP = continuous positive airway pressure; RR = relative risk.

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Figure 4.
Risk for in-hospital mortality as a function of acute MI or ischemia at admission, comparing continuous positive airway pressure with standard therapy.

Regression equation: log risk ratio = 0.103 – 1.906 × (percentage of patients with acute MI or ischemia at admission). The crude risk estimates from the individual studies are plotted along with their regression line. MI = myocardial infarction.

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Figure 5.
Weight of the 3CPO (Three Interventions in Cardiogenic Pulmonary Oedema) trial as a function of pooled RRs with their associated 95% CIs.

Calculated according to the formula ln(Pooled RR) = (1 − wt) × ln(RR1) + wt × ln(RR2), where wt = weight, RR1 = meta-analysis of other trials by using the Mantel–Haenszel method, and RR2= meta-analysis of the 3CPO trial by using the inverse variance method. MI = myocardial infarction; RR = relative risk.

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Tables

References

Letters

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Comments

Submit a Comment
Meta-analysis of small heterogenous trials versus single large RCT
Posted on May 18, 2010
Steve W Goodacre
University of Sheffield
Conflict of Interest: None Declared

As co-investigators on the 3CPO trial (1), we were interested in the meta-analysis of non-invasive ventilation by Weng and colleagues (2). We would highlight that the authors of the meta-analysis have misrepresented two quality criteria and the prevalence of myocardial infarction in relation to the 3CPO trial. First, they have incorrectly stated that the 3CPO trial did not have allocation concealment. Although an open trial, recruited patients were allocated to a treatment group by a telephone randomisation system after they had been irreversibly entered into the trial. Second, the dropout rate for 3CPO is quoted as 19.4%. Presumably this is the 205/1055 who did not complete their allocated treatment. However, this is not the dropout rate according to the PEDro scale used by the authors, for which the relevant item is that measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups. The primary outcome for 3CPO was recorded for 1062/1069 subjects (99%). Third, they state that only about 20% of [3CPO] trial patients had myocardial ischemia or infarction, whereas according to the Universal definition around 50% of the 3CPO population had myocardial infarction. We have not checked whether similar errors have been made in relation to other studies in their review but we would request that the subgroup analysis on study quality and baseline myocardial infarction or ischaemia should be corrected for our study.

The meta-analysis raises an interesting point, why did the results of the 3CPO trial differ from previous studies? We believe that there is marked heterogeneity of the trials included in the meta-analysis (clinical setting, study population, entry criteria, etc), and that the 3CPO trial asked a different type of research question. It was a pragmatic trial aimed at determining effectiveness of non-invasive ventilation as a first- line treatment for severe acute cardiogenic pulmonary oedema in patients presenting to the Emergency Department. Selection of patients and treatment protocols were designed to replicate routine practice and, as noted, crossover to non-invasive ventilation was allowed for patients who did not respond to standard therapy. The 3CPO trial showed that standard oxygen therapy with non-invasive ventilation for those who do not respond to initial treatment produces similar mortality outcomes to non-invasive ventilation as a first-line treatment. It does not exclude a role for non- invasive ventilation in certain patients or negate previous conclusions that non-invasive ventilation can improve symptoms and clinical outcome.

References

1. Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J; 3CPO Trialists. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359:142-51.

2. Weng CL, Zhao Y-T, Liu O-H, Fu C-J, Sun F, Ma Y-L, Chen Y-W, He O- Y. Meta-analysis: Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema. Ann Intern Med 2010; 152: 590-600.

Conflict of Interest:

We are co-investigators on the 3CPO Trial

Re:Meta-analysis of small heterogenous trials versus single large RCT
Posted on June 13, 2010
Yun-Tao Zhao
MD,PhD
Conflict of Interest: None Declared
We thank Dr. Goodacre and colleagues for their careful review and comments. We unfortunately judged allocation concealment incorrectly for 3CPO and two other studies. (1-3). Subgroup meta-analysis of trials with allocation concealment properly classified for these trials still demonstrate an advantage of CPAP over standard therapy for mortality (relative risk = 0.58 [CI, 0.37 to 0.90]) and need for mechanical intubation (relative risk = 0.43 [CI, 0.28 to 0.66]).

We also thank Dr. Goodacre for pointing out that the primary outcome in 3CPO was assessed in almost all participants. We did indeed count cross-overs as dropouts in error. Results of cumulative meta-analysis by trial quality do not substantively change when we properly classified all trials with allocation concealment and when we counted the 3CPO trial as having dropouts <15% (data not shown).

We based assessments for myocardial infarction on traditional WHO criteria rather than the Universal definition because most other trials that reported myocardial infarction or ischemia data used WHO criteria. We note that most trials of non-invasive ventilation included in our analysis were published prior to consensus reporting about the Universal definition. It would be difficult to classify cases from those reports by the Universal definition and perform reliable analyses using the new definition. We note that the legend to Figure 4 specifies the regression equation readers can use to estimate the risk ratio for mortality with CPAP compared to standard therapy using different proportions of trial participant with acute myocardial infarction or ischemia. Interested readers can contact us for regression equations to assess changes in risk estimates with changes in proportion for the reviewâ"™s other comparisons (bilevel ventilation v. standard therapy, CPAP v. bilevel ventilation) and outcome (need for intubation).

We agree that patient variability and differences in trial design, inclusion and exclusion criteria, and target populations are important in summarizing this body of evidence and stand by our overall conclusion that available evidence supports the use of non-invasive ventilation for patients with acute cardiogenic pulmonary edema.

Yun-tao Zhao. Ph.D, M.D. Health Science Center Peking University

References

1. Gary A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J: 3CPO Trialists. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008:359:142-51.

2.Nava S, Carbone G, DiBattista N, Bellone A, Baiardi P, Cosentini R, et al. Noninvasive ventilation in cardiogenic pulmonary edema: a multicenter randomized trial. Am J Respir Crit Care Med. 2003;168(12):1432-7. [12958051].

3. Bersten AD, Holt AW, Vedig AE, Skowronski GA, Baggoley CJ. Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med. 1991;325(26):1825-30. [1961221].

Conflict of Interest:

None declared

Re:Meta-analysis of small heterogenous trials versus single large RCT
Posted on June 13, 2010
Yun-Tao Zhao
MD, PhD
Conflict of Interest: None Declared

Table. The result of subgroup meta-analysis by allocation concealment.

 

Allocation concealment

No. of studies

RR(95% CI)

Mortality

 

 

 

CPAP vs. standard therapy

Yes

10

0.58(0.37 to 0.90)

 

No

3

0.68(0.25 to 1.83)

Bilevel ventilation vs. standard therapy

Yes

5

0.83(0.58 to 1.19)

 

No

4

0.72(0.23 to 2.19)

Bilevel ventilation vs. CPAP

Yes

9

1.09(0.72 to 1.67)

 

No

3

0.55(0.19 to 1.63)

 

N/A

2

1.12(0.16 to 7.71)

Intubation rate

 

 

 

CPAP vs. standard therapy

Yes

10

0.43(0.28 to 0.66)

 

No

4

0.40(0.19 to 0.84)

Bilevel ventilationvs. standard therapy

Yes

5

0.56(0.23 to 1.41)

 

No

3

0.50(0.26 to 1.16)

 

N/A

1

0.37(0.13 to 1.10)

Bilevel ventilation vs. CPAP

Yes

9

1.81(0.92 to 3.57)

 

No

4

0.34(0.09 to 1.26)

 

N/A

2

1.59(0.21 to 12.26)

New MI

 

 

 

CPAP vs. standard therapy

Yes

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