J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 8, Number 5, May 2016, pages 361-366

Unresolved or Contradictory Issues About Management of Patients With Patent Foramen Ovale and Previous Cryptogenic Stroke: Additional Randomized Controlled Trials Are Eagerly Awaited

Figure 1. PFO occluding devices. (a) Gore Helex septal occluder; (b) STARFlex PFO implant device; (c) Amplatzer PFO occluder.

**Table 1.** Strengths and Limitations of Meta-Analyses of PFO Closure RCTs for Stroke Recurrence
Study	RCTs only	ITT subset only	Random effect statistical model	Analysis of potential adverse events	Conclusion beneficial
ITT: intention-to-treat; RCT: randomized controlled trial.
Ntaios et al [4]	Yes	No	No	Yes	No overall; yes with Amplatzer
Pineda et al [5]	Yes	No	Yes	Yes	No overall; yes as treated
Kitsios et al [6]	Yes	No	Yes	No	Inconclusive
Riaz et al [7]	Yes	No	Yes	Yes	No overall; yes as treated
Hakeem et al [8]	Yes	No	Yes	Yes	Probably
Kwong et al [9]	Yes	Yes	Yes	Yes	No
Nagaraja et al [10]	Yes	Yes	Yes	Yes	No
Rengifo-Moreno et al [11]	Yes	No	No	Yes	Yes
Khan et al [12]	Yes	No	No	Yes	Yes
Spencer et al [13]	Yes	No	Yes	Yes	No
Wolfrum et al [14]	No	No	Yes	Yes	No
Capodanno et al [15]	No	Yes	Yes	Yes	No overall; yes with Amplatzer
Pandit et al [16]	Yes	Yes	No	No	No overall; yes with Amplatzer
Udell et al [17]	Yes	Yes	Yes	Yes	No
Li et al [18]	Yes	Yes	Yes	Yes	No

Table 1. Strengths and Limitations of Meta-Analyses of PFO Closure RCTs for Stroke Recurrence

Study

RCTs only

ITT subset only

Random effect statistical model

Analysis of potential adverse events

Conclusion beneficial

ITT: intention-to-treat; RCT: randomized controlled trial.

Ntaios et al [4]

Yes

No overall; yes with Amplatzer

Pineda et al [5]

Yes

No overall; yes as treated

Kitsios et al [6]

Yes

Inconclusive

Riaz et al [7]

Yes

No overall; yes as treated

Hakeem et al [8]

Yes

Probably

Kwong et al [9]

Yes

Nagaraja et al [10]

Yes

Rengifo-Moreno et al [11]

Yes

Khan et al [12]

Yes

Spencer et al [13]

Yes

Wolfrum et al [14]

Yes

Capodanno et al [15]

Yes

No overall; yes with Amplatzer

Pandit et al [16]

Yes

No overall; yes with Amplatzer

Udell et al [17]

Yes

Li et al [18]

Yes

**Table 2.** Approaches Used for Assessing a Randomized Controlled Trial: “Intention to Treat”, “As Treated” and “Per Protocol”
Intention to treat	Randomized clinical trials analyzed by the “intention to treat” (ITT) approach provide unbiased comparisons among the treatment groups. “Intention to treat” analyses are done to avoid the effects of crossover and dropout, which may break the random assignment to the treatment groups in a study. ITT analysis provides information about the potential effects of treatment policy rather than on the potential effects of specific treatment. Since it started in the 1960s, the principle of ITT has become widely accepted for the analysis of controlled clinical trials. However, full application of ITT analysis can only be performed where there are complete outcome data for all randomized subjects.
As treated	“As treated” analysis has the general idea of comparing the subjects with the treatment regimen that they received. It does not consider which treatment they were assigned for the treatment.
Per protocol	The “per protocol” analysis, also known as an “on-treatment” analysis, can only be restricted to the participants who fulfill the protocol in the terms of the eligibility, interventions, and outcome assessment. Indeed, the “per protocol” analysis restricts the comparison of the treatments to the ideal patients, that is, those who adhered perfectly to the clinical trial instructions as stipulated in the protocol. However, by restricting the analysis to a selected patient population, it does not show the practical value of the drug or method that has to be tested.

Table 2. Approaches Used for Assessing a Randomized Controlled Trial: “Intention to Treat”, “As Treated” and “Per Protocol”

Intention to treat

Randomized clinical trials analyzed by the “intention to treat” (ITT) approach provide unbiased comparisons among the treatment groups. “Intention to treat” analyses are done to avoid the effects of crossover and dropout, which may break the random assignment to the treatment groups in a study. ITT analysis provides information about the potential effects of treatment policy rather than on the potential effects of specific treatment. Since it started in the 1960s, the principle of ITT has become widely accepted for the analysis of controlled clinical trials. However, full application of ITT analysis can only be performed where there are complete outcome data for all randomized subjects.

As treated

“As treated” analysis has the general idea of comparing the subjects with the treatment regimen that they received. It does not consider which treatment they were assigned for the treatment.

Per protocol

The “per protocol” analysis, also known as an “on-treatment” analysis, can only be restricted to the participants who fulfill the protocol in the terms of the eligibility, interventions, and outcome assessment. Indeed, the “per protocol” analysis restricts the comparison of the treatments to the ideal patients, that is, those who adhered perfectly to the clinical trial instructions as stipulated in the protocol. However, by restricting the analysis to a selected patient population, it does not show the practical value of the drug or method that has to be tested.