The Journal for Nurse Practitioners
Volume 5, Issue 3 , Pages 176-184, March 2009

Evaluation of Thiazolidinediones on Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus: A Systematic Review

  • Joyce Yu-Chia Lee

      Affiliations

    • All authors are employed in the Department of Pharmacy at the National University of Singapore.
    • A board-certified pharmacotherapy specialist, Joyce Yu-Chia Lee, PharmD, BCPS, is an assistant professor in the department and a clinical pharmacist at National Healthcare Group Polyclinics.
    • ,
  • Tan Miao Ling Ferlyn

      Affiliations

    • All authors are employed in the Department of Pharmacy at the National University of Singapore.
    • Tan Miao Ling Ferlyn is a preregistration community pharmacist at Guardian Health and Beauty Pharmacy.
    • ,
  • Alexandre Chan

      Affiliations

    • All authors are employed in the Department of Pharmacy at the National University of Singapore.
    • A board-certified pharmacotherapy specialist and oncology pharmacist, Alexandre Chan, PharmD, BCPS, BCOP, is an assistant professor in the department and a clinical pharmacist at the National Cancer Centre Singapore.

Article Outline

Abstract 

Diabetes mellitus (DM) is a chronic disease regarded as a risk equivalent of coronary heart disease. Although pharmacologic therapy is an effective way to manage DM, a meta-analysis published in 2007 found clinically significant associations between rosiglitazone and increased myocardial infarction and cardiovascular deaths. In addition, thiazolidinediones (TZDs) have been shown to exert different effects on lipid profiles. The primary objective is to evaluate the effects of rosiglitazone on cardiovascular outcomes in patients with type 2 DM. The secondary objective is to assess the effects of rosiglitazone and pioglitazone on lipid profiles. Studies were obtained from selected electronic databases. Inclusion criteria for primary objective included randomized controlled trials with duration ≥ 24 weeks and primary or secondary outcome evaluating safety assessment. For the secondary objective, all randomized controlled trials conducted over the past 10 years comparing rosiglitazone versus pioglitazone and rosiglitazone/pioglitazone monotherapy versus placebo were included. Clinical trials with longer duration and improved quality, specifically designed to assess and evaluate the effects of rosiglitazone on cardiovascular risks, need to be conducted. In the interim, rosiglitazone appeared safe to be continued with close monitoring in patients without previous or current cardiovascular diseases. When the use of TZDs is deemed necessary, pioglitazone may be a better option, based on the available cardiovascular safety data and its potentially beneficial effects on lipid profiles.

Keywords:  Cardiovascular , cholesterol , rosiglitazone , systematic review , thiazolidinediones , type 2 diabetes mellitus

 

Rosiglitazone (Avandia, GlaxoSmithKline, USA) and pioglitazone (Actos, Takeda, Japan) are thiazolidinediones (TZDs) indicated as an adjunctive treatment with diet and exercise in patients with type 2 diabetes mellitus (T2DM).1 Currently, guidelines for treatment of T2DM recommend TZDs to be used as one of the second-line treatments should metformin and lifestyle interventions fail to achieve glucose control.2, 3 Common adverse effects of TZDs include weight gain, hepatotoxicity, and fluid retention, which has set a new boxed warning by the Food and Drug Administration (FDA) for causing or worsening heart failure.4 Initiation of TZDs in patients with established New York Heart Association (NYHA) class III or IV is contraindicated.

In June 2007, a meta-analysis found an association between rosiglitazone and increased cardiac risks in patients with T2DM; it concluded that rosiglitazone was associated with an approximately 43% and 64% of increased risk for myocardial infarction (MI) and cardiovascular (CV) deaths, respectively.5 These findings attracted a great deal of publicity and set yet another boxed warning specifically to the rosiglitazone package insert by the FDA about the risk of myocardial ischemia for the treatment of T2DM.4

The true association between rosiglitazone and CV outcomes, however, is still controversial. For instance, the interim analysis from the RECORD study showed no statistically significant differences between the rosiglitazone-treated group and the control group regarding MI and deaths from CV causes.6 The usage of rosiglitazone in treating patients with DM, therefore, is still being questioned by many clinicians. Currently, literature on the association between rosiglitazone and CV events are mixed and inconclusive.6, 7, 8

In addition to the questionable effects of TZDs on the CV outcomes, clinical trials have also shown different effects of TZDs on lipid profiles.9 Although the exact mechanism of how TZDs may affect the lipids is yet to be elucidated, the association between uncontrolled serum lipids and CV events due to the formation of atherosclerotic plaque is well established.10 Because such findings may be particularly important in a populaton at high risk of cardiovascular events, any effects of TZDs on lipid profiles should also be considered.

This systematic review was conducted to further evaluate and assess the safety data of rosiglitazone on all events including CV outcomes. The primary objective of this study was to evaluate descriptively the effects of rosiglitazone on CV outcomes in patients with T2DM.5, 6 The secondary objective was to determine the effects of TZDs on all lipid parameters.

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Methods 

Search Strategy 

A literature search for the evaluation of primary and secondary objectives was conducted using PubMed, Cochrane Library, and International Pharmaceutical Abstracts databases. The search keywords for the primary objective included thiazolidinediones, rosiglitazone, cardiovascular, myocardial infarction, randomized controlled trial, and systematic review. The search keywords for the secondary objective included thiazolidinediones, rosiglitazone, pioglitazone, lipids, lipoprotein, and cholesterol.

Articles identified based on the use of individual and combined keywords were excluded from the initial screening if their title or abstract were not relevant to the context of this study. The full texts of the articles were retrieved for further evaluation when their title and abstract were not excluded with certainty. No authors were contacted for additional data.

Criteria for Study Selection: Primary Objective 

The inclusion criteria included English-language articles with full texts published from August 2007 to December 2007, randomized controlled trials with duration of more than or equal to 24 weeks, studies comparing rosiglitazone 2 mg to 8 mg/day as monotherapy or in combination with other anti-diabetic medications including insulin, presence of a control group using any anti-diabetic medications other than rosiglitazone, trials that included adult patients with hemoglobin A1c (HbA1c) − 7.0% or fasting plasma glucose (FPG) greater than 126 mg/dL, and studies with primary or secondary outcomes focusing on safety assessment, both CV and non-CV adverse effects or events.

Studies involving patients with congestive heart failure (CHF) New York Heart Association (NYHA) class III or IV, clinically significant hepatic disease, or uncontrolled hypertension and/or lipid profile, as defined by the author(s) of the article, were excluded.

Criteria for Study Selection: Secondary Objective 

The study selection was focused on randomized controlled trials published from 1998 to 2007 that studied the effects of rosiglitazone versus pioglitazone, and TZD monotherapy versus placebo on lipid profiles. For the trials that studied the effects of TZD monotherapy versus placebo, studies were excluded if subjects were on other anti-diabetic agents or lipid-lowering drugs concomitantly throughout the trial period.

Assessment Of Quality Of Studies 

The quality of all randomized controlled trials in this study was assessed using the CONSORT (Consolidated Standards of Reporting Trials) checklist.11 The CONSORT statement consists of a 22-item checklist and covers a trial's design, conduct, analysis, and interpretation.12

Primary Objective Results 

Study characteristics. A total of 157 potential articles were found using the selected keywords. Of the 157 articles, 111 were excluded based on the study title and abstract content. Forty-six (29%) articles were then retrieved and 15 studies met the selection criteria.6, 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Lack of data for drug safety and patients with uncontrolled hypertension and/or dyslipidemia were the main reasons of exclusion.

Of the 15 studies, 7 were published between 2000 and 2004, while the remaining articles were published between 2005 and 2007. The duration of trials varied from 24 weeks to 4 years. Ten studies were conducted over a period of less than or equal to 26 weeks, and all studies did not have a post-intervention follow-up period. Sample size of the studies ranged from 203 to 4447 patients, and most studies were carried out in the United States and European countries. Six studies investigated rosiglitazone as monotherapy versus another monotherapy (metformin, sulfonylurea, or placebo), and 8 studies evaluated rosiglitazone in combination with other anti-diabetic agents. One study investigated rosiglitazone both as monotherapy and combination therapy with another antidiabetic agent(s). There were a total of 23 rosiglitazone-treated groups and 16 control groups from the 15 studies. The doses of rosiglitazone investigated were classified into maximum daily doses of 2 mg, 4 mg, and 8 mg/day. Ten of 15 studies investigated the change in HbA1c from baseline as primary outcome. Secondary outcomes included changes in FPG, serum lipids, insulin, C-peptide, and safety assessment.

Patient characteristics. All studies reported similar baseline patient characteristics. Mean age of patients in the rosiglitazone-treated groups and control groups ranged from 52.0 to 64.3 years and from 53.0 to 63.9 years, respectively. The number of male patients was greater than female patients in both the rosiglitazone-treated groups and the control groups. Other baseline characteristics of patients are shown in Table 1.

Table 1. Mean Baseline Characteristics of Patients in Rosiglitazone-Treated Groups and Control Groups
ControlRosiglitazone 2 mg/dayRosiglitazone 4 mg/dayRosiglitazone 8 mg/day
No. of groups161616
BMI (kg/m2)28.1-34.628.028.3-32.128.7-34.4
HbA1c (%)7.35-9.509.208.20-9.237.36-9.20
FPG (mg/dL)153-268203191-229151-257
Duration of diabetes (years)4.6-11.77.04.8-12.75.3-12.5

BMI, body mass index; FPG, fasting plasma glucose.

Safety. Specific incidence of MI events and CV deaths were reported in few studies (Table 2). No CV deaths were reported in both the rosiglitazone 2 mg/day and 4 mg/day groups. Among the 6 rosiglitazone 8 mg/day groups that reported MI events, one was statistically insignificant (P = 0.5)6 and the clinical significance of the remaining groups was not reported.8, 13, 14, 15, 24 Of the 5 rosiglitazone 8 mg/day groups that reported CV deaths, 2 were statistically insignificant (P = 0.85 and P = 0.46),6, 14 while the clinical significance of the remaining groups was not reported.8, 13, 17 Congestive heart failure (CHF) was reported in one study with rosiglitazone 4 mg/day, but the statistical significance was not reported.21 Among the 6 rosiglitazone 8 mg/day groups documented with CHF, 2 groups were statistically significant (P = 0.006 and P ≤ 0.05),6, 8 and one group was statistically insignificant (P = 0.858).14 The remaining 3 groups reported the event to be unrelated to rosiglitazone.13, 15, 20

Table 2. Incidence of MI, CV Deaths, and CHF in Patients in Rosiglitazone and Control Groups
Cardiovascular Adverse EventsRosiglitazone 2 mg/day (n = 1)Rosiglitazone 4 mg/day (n = 6)Rosiglitazone 8 mg/day (n = 16)
No. of groups with MI reported006
Range of proportion of MI events in rosiglitazone-treated group——1-43/110-2220
Range of proportion of MI events in control group——0-37/114-2227
No. of groups with CV deaths reported125
Range of proportion of CV deaths reported in rosiglitazone-treated group0/1990/183-2000-29/110-2220
Range of proportion of CV deaths reported in control group0/1920/192-2070-35/114-2227
No. of groups with CHF reported016
Range of proportion of CHF reported in rosiglitazone-treated group—2/1071-38/105-2220
Range of proportion of CHF reported in control group—1/1070-19/107-2227

Proportion of events is defined as number of patients experiencing the event/total number of patients in the rosiglitazone-treated group. CHF, congestive heart failure; CV, cardiovascular; MI, myocardial infarction.

In addition, other cardiac events, such as incidence of stroke, ventricular tachycardia/fibrillation, and ischemic attack were also reported in 6 studies using a higher dose of rosiglitazone at 8 mg/day.14, 18, 23, 24, 25 The significance of these events, however, was either not reported, or similar to the control groups. Overall, no significant CV outcomes were observed for up to 24 weeks of rosiglitazone therapy.

In general, more adverse events were reported with rosiglitazone-treated groups. CV and non-CV adverse events were more likely in patients taking higher doses of rosiglitazone (Table 3).

Table 3. Non-Cardiovascular Adverse Events in All Groups
Control (n = 16)Rosiglitazone 2 mg/day (n = 1)Rosiglitazone 4 mg/day (n = 6)Rosiglitazone 8 mg/day (n = 16)
No. of GroupsHypoglycemiaHypoglycemiaHypoglycemiaHypoglycemia
(10)(1)(3)(11)
EdemaWeight gainEdemaEdema
(10)(1)(5)(11)
Weight gainDecreased hematocritWeight gainWeight gain
(9)(1)(5)(12)
—Decreased hemoglobinDecreased hematocritDecreased hemoglobin
(1)(6)(9)
——Decreased hemoglobinCardiac-related
(6)(9)

Efficacy. At higher doses, rosiglitazone appeared to be associated with greater reduction of both FPG and HbA1c. Statistically significant changes in HbA1c (−0.025 to −1.51%) and FPG (−17 to 94 mg/dL) were observed in most of the rosiglitazone-treated groups regardless of dose.

Quality of studies. The number of items from the 15 studies that met the 22 criteria of the CONSORT checklist ranged from 8 to 17.6, 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Items that were missing or failed to meet the CONSORT standards included generation of sequence in randomization, interpretation, and outcomes and estimation (67%); flow of participants through each stage of the study (73%); ancillary analyses (80%); allocation of concealment in randomization (87%); method of masking and generalizability (93%); and implementation of randomization and periods of recruitment (100%).26, 27

Secondary Objective Results 

Study and patient characteristics. Fourteen studies met the selection criteria for the secondary objective of this study. Of the 14 studies, 4 studies compared rosiglitazone with pioglitazone,28, 29, 30, 31 6 compared rosiglitazone monotherapy with placebo,19, 32, 33, 34, 35, 36 and 4 compared pioglitazone monotherapy with placebo.37, 38, 39, 40

The rosiglitazone/pioglitazone monotherapy versus placebo studies were published between 1999 and 2004, and the trial durations ranged from 8 to 26 weeks. The rosiglitazone versus pioglitazone studies were published between 2002 and 2007, with trial durations ranging from 4 months to 1 year.

In the rosiglitazone monotherapy studies, the total number of patients in the rosiglitazone and placebo groups ranged from 14 to 303 and 11 to 110, respectively. The doses of rosiglitazone investigated were classified into 6 maximum daily doses of 0.1 to 12 mg/day. Patients were well matched in their baseline characteristics in all studies. The mean age of patients treated with rosiglitazone and placebo ranged from 54.0 to 63.0 years and from 56.0 to 62.3 years, respectively. The mean baseline BMI was similar in both groups, ranging from 28.9 to 30.4 kg/m2.

In the pioglitazone monotherapy studies, the total number of patients in the pioglitazone and placebo groups ranged from 11 to 84 and 11 to 79, respectively. The pioglitazone dosages investigated were classified into 4 maximum daily doses of 7.5 to 45 mg/day. All patients were well matched in their baseline characteristics. The mean age of patients treated with pioglitazone and placebo ranged from 53.5 to 61.4 years and from 58.0 to 62.6 years, respectively. The mean baseline BMI was similar in both groups, ranging from 28.9 to 31.5 kg/m2.

Among the comparative studies of rosiglitazone and pioglitazone, the doses of rosiglitazone and pioglitazone ranged from 2 mg to 8 mg/day and 15 mg to 45 mg/day, respectively. Of the 4 studies, 2 included patients taking lipid-lowering drugs concurrently.29, 31 In one study, 58% and 60% of patients in the rosiglitazone and pioglitazone group, respectively, were on HMG-CoA reductase inhibitor throughout the 4-month study period.29 In another study, the number of patients and the type of lipid-lowering medications, however, were not reported.31 There was no statistically significant difference between the treatment groups with respect to baseline characteristics in all 4 studies that looked at rosiglitazone versus pioglitazone therapy. The mean age of patients treated with rosiglitazone and pioglitazone ranged from 54.0 to 57.1 years and from 53.0 to 57.8 years, respectively. The mean baseline BMI was similar, ranging from 24.3 to 35.6 kg/m2.

Effects of TZDs on lipid parameters. In the rosiglitazone versus placebo studies, treatment with 0.1 mg to 2 mg/day of rosiglitazone did not show statistically significant changes in all lipid parameters when compared to placebo. Most of the rosiglitazone 4 mg, 8 mg, and 12 mg/day groups did not make statistically significant changes in HDL or TG level when compared to placebo. The majority of rosiglitazone groups at doses ranging from 4 mg to 8 mg/day; however, showed statistically significant changes in TC and LDL when compared to placebo. Overall, rosiglitazone resulted in an increase in all lipid parameters, with statistically significant increase in TC (+15 to +33 mg/dL) and LDL (+8 to +28 mg/dL).

In the pioglitazone versus placebo studies, treatment with 7.5 mg to 15 mg/day of pioglitazone did not show any statistically significant changes in all lipid parameters when compared to placebo. Statistically significant changes in HDL (+4 to +6 mg/dL) and TG (−36 to −54 mg/dL) were observed in most of the pioglitazone 30 mg/day groups. Statistically significant changes in HDL and TG, however, were not observed in the majority of the pioglitazone 45 mg/day groups. With an exception of a statistically significant increase in HDL and decrease in TG in patients taking pioglitazone 30 mg/day, pioglitazone at other doses did not affect the overall metabolism of lipid parameters.

Overall, all changes were statistically significant when comparing the effects of rosiglitazone and pioglitazone on lipid parameters (Table 4). Any changes in lipid parameters appeared to take effect anywhere from 24 to 48 weeks after the initiation of TZDs.29, 30

Table 4. Mean Changes in Lipid Parameters (mg/dL) from Baseline in Patients from Studies Comparing Rosiglitazone with Pioglitazone
ArticleRosiglitazonePioglitazoneP-value
Derosa 2006
Dose4 mg/day (n = 42)15 mg/day (n = 45)
TC+29*−12*< 0.05
LDL+20*−15*< 0.05
HDL+0.7+6*< 0.05
TG+29*−35*< 0.05
Derosa 2007†
Dose4 mg/day (n = 48)15 mg/day (n = 48)
TC+8−19*< 0.05
LDL+3−8*< 0.05
HDL−1+4*< 0.05
TG−3−42*< 0.05
Goldberg 2005
Dose4 mg/day for 1st 12 weeks, 8 mg/day for 2nd 12 weeks30 mg/day for 1st 12 weeks, 45 mg/day for 2nd 2 weeks
(n = 366)(n = 369)
TC+28*+9*< 0.001
LDL+21*+12*< 0.001
HDL+2*+5*< 0.001
TG+13−52*< 0.001
Khan 2002†
Dose2, 4, 8 mg/day (n = 60)15, 30, 45 mg/day (n = 67)
TC+5−21*< 0.01
LDL−2−18*< 0.01
HDL+1+2*< 0.05
TG+6−15*< 0.05

† Study that included patients on lipid-lowering drugs. P-value is for comparison between the 2 treatment groups.

* P ≤0.05 versus baseline level. HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.

Quality of studies 

The number of items from the 14 studies that met the 22 criteria of the CONSORT checklist ranged from 7 to 13.19, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 Items that were missing or failed to meet the CONSORT standards include number of participants analyzed (57%); interventions (71%); allocation concealment, interpretation, and generalizability (86%); sample size, sequence generation for randomization, and flow of participants in each stage (93%); and implementation of randomization, methods of masking, recruitment, outcomes and evaluation, and ancillary analyses (100%).

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Discussion 

This systematic review was conducted to further analyze the association between rosiglitazone and its CV risks by setting the inclusion and exclusion criteria based on the strengths and limitations from recent studies.5, 6 In this review, the use of standardized inclusion and exclusion criteria, such as selecting randomized controlled trials with longer study period and primary or secondary outcomes focusing on safety assessment, and excluding studies with patients with uncontrolled hypertension and/or hyperlipidemia or previous history of CV events, have all set this study apart from the previous studies. Although the more stringent inclusion and exclusion criteria have brought about only few qualifying articles as a result, much effort was put into selecting the most appropriate articles for the evaluation of this study.

CONSORT checklist, which was not utilized in the previous studies, was also carried out to evaluate the quality of all articles used in this study.5, 6, 7, 8 Up to 34% of the articles from the primary objective and up to 79% of the articles from the secondary objective failed to fulfill more than half of the items on the checklist. This indicated that more qualitative randomized trials are required. Although other tools may be used as a means of method to assess the quality of the clinical trials included in this systematic review, CONSORT was selected based on its validity and credibility, and the fact that it is specifically designed for randomized controlled trials.42, 43

In this study, the incidence of adverse events, with CV-related events in particular, appeared to be dose dependent. The number of MI events, CV deaths, and worsening of CHF reported was much higher in the rosiglitazone 8 mg/day groups than the rosiglitazone 2 mg/day and 4 mg/day groups. While the exact mechanism of action of rosiglitazone on MI or CV deaths are yet to be elucidated, the worsening of CHF is due to rosiglitazone-induced fluid retention and expansion of plasma volume.44, 45, 46

Although all studies assessed the safety profiles of rosiglitazone, follow-up periods were not conducted, and the range of safety profiles evaluated were not clearly stated or specified. For example, MI and/or CV deaths were not reported in 11 of 15 studies.25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 “Not reported” may simply indicate that the patients did not experience any of such events. However, CV adverse effects cannot be ruled out completely. They could have been overlooked if these adverse effects were not specifically assessed. Lack of post-intervention follow-up period in all studies also made it difficult to determine any long-term effects of rosiglitazone on CV events. For these reasons, the association of rosiglitazone with CV events can only be confirmed with more clinical trials specially designed to assess and report the occurrence of CV outcomes in rosiglitazone-treated patients.

In selecting articles for the review of effects of TZDs on lipid profiles, certain glucose-lowering drugs such as metformin were excluded, due to its potential benefits on lipid parameters.47 Patients who were on concurrent lipid-lowering medications were also excluded to ensure that any change in lipid-lowering effects, if any, were solely due to TZDs. While neither pioglitazone nor rosiglitazone changed the lipid profile at lower doses, pioglitazone at higher doses produced beneficial effects on all lipid parameters. Rosiglitazone, on the other hand, at doses greater than or equal to 4 mg/day was associated with an increase in LDL. However, whether the magnitudes of these changes from TZDs on lipid profile are sufficient to produce any clinically significant CV benefits or risks still need to be determined.

Several limitations must be addressed in this study. First, publication biases could not be assessed using statistical methods such as funnel plots, as the nature of this systematic review is purely descriptive; outcome-reporting biases and biases due to excluding non-English trials also need to be acknowledged. Second, the conclusions drawn from this study was based on a descriptive summary of a small number of articles; therefore, this may have weakened the translation of the study conclusion into the current practice. However, due to the dissimilarities in the clinical trials involved, the combination of the results would not be meaningful and we refrained from statistically combining the results in this study.48, 49 A meta-analysis specifically designed or statistically powered to evaluate the cardiovascular events would provide a stronger association between rosiglitazone and CV events. However, more clinical trials addressing the cardiovascular safety are needed for the meta-analysis to take place.

Lastly, the focus of this study was on the effects of rosiglitazone and TZDs on the CV outcomes and lipid profiles, respectively. Therefore, the effects of pioglitazone on the CV events could not be determined from this study. However, based on the PROactive trial, which was specifically designed to evaluate the effect of pioglitazone on cardiovascular events and mortality in patients at high risk for macrovasuclar complications, pioglitazone was associated with a significantly lower risk of death, MI, or stroke; the results from a subgroup analysis of the PROactive trial further supported this finding.50, 51

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Conclusion 

Although it is not known to date whether rosiglitazone can be used safely in all patients with DM, rosiglitazone appeared safe to be continued with close monitoring in patients without previous or current cardiovascular diseases based on this study. In addition, when the use of TZDs is deemed necessary, pioglitazone may be a better option of the TZDs based on the cardiovascular safety data that are currently available and its potentially beneficial effects on lipid profiles.

This systematic review was conducted using selection criteria that were more stringent compared to the previous studies. However, due to the small number of articles qualified for the evaluation and descriptive nature of this study, more research and clinical trials with improved quality of design and statistical analysis are advised to confirm the conclusions drawn from this study.

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Uncited reference 

  1. Altman DC . Better reporting of randomized controlled trials: The CONSORT statement . BMJ . 1996;313(7057):570–571

 In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.

PII: S1555-4155(08)00480-7

doi:10.1016/j.nurpra.2008.09.004

The Journal for Nurse Practitioners
Volume 5, Issue 3 , Pages 176-184, March 2009

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