RCT
Potential PURL Review Form
PURL Jam Version
Version #11 October 29, 2009
PURLs Surveillance System
Family Physicians Inquiries Network
SECTION 1: Identifying Information for Nominated Potential PURL[to be completed by PURLs Project Manager]
1. Citation / Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial.
Ahimastos AA, Walker PJ, Askew C, Leicht A, Pappas E, Blombery P, Reid CM, Golledge J, Kingwell BA.
JAMA. 2013 Feb 6;309(5):453-60. doi: 10.1001/jama.2012.216237.
PMID:
23385271
2. Hypertext link to PDF of full article / http://www.ncbi.nlm.nih.gov/pubmed/?term=Effect+of+Ramipril+on+Walking+Times+and+Quality+of+Life+Among+Patients+With+Peripheral+Artery+Disease+and+Intermittent+Claudication+A
3. First date published study available to readers / 2/6/13
4. PubMed ID / 23385271
5. Nominated By / Sarah-Anne SchumannMike MendozaJim StevermerBernard EwigmanOther Other:
6. Institutional Affiliation of Nominator / University of ChicagoUniversity of MissouriUniversity of North CarolinaUniversity of MinnesotaOther Other:
7. Date Nominated / 2/6/13
8. Identified Through / BMJ OnlineDynaMedInfoPOEMsOther Other: TOC
9. PURLS Editor Reviewing Nominated Potential PURL / Kate RowlandBernard EwigmanJohn HicknerOther Other:
10. Nomination Decision Date / 2/14/13
11. Potential PURL Review Form (PPRF) Type / Cohort StudyMetaanalysisRCTDiagnostic Test
12. Other comments, materials or discussion
13. Assigned Potential PURL Reviewer / Nina Rogers
14. Reviewer Affiliation / University of ChicagoUniversity of MissouriUniversity of MinnesotaOther Other:
15. Date Review Due / 3/14/13
16. Abstract / Approximately one-third of patients with peripheral artery disease experience intermittent claudication, with consequent loss of quality of life.
OBJECTIVE:
To determine the efficacy of ramipril for improving walking ability, patient-perceived walking performance, and quality of life in patients with claudication.
DESIGN, SETTING, AND PATIENTS:
Randomized, double-blind, placebo-controlled trial conducted among 212 patients with peripheral artery disease (mean age, 65.5 [SD, 6.2] years), initiated in May 2008 and completed in August 2011 and conducted at 3 hospitals in Australia.
INTERVENTION:
Patients were randomized to receive 10 mg/d of ramipril (n = 106) or matching placebo (n = 106) for 24 weeks.
MAIN OUTCOME MEASURES:
Maximum and pain-free walking times were recorded during a standard treadmill test. The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively.
RESULTS:
At 6 months, relative to placebo, ramipril was associated with a 75-second (95% CI, 60-89 seconds) increase in mean pain-free walking time (P < .001) and a 255-second (95% CI, 215-295 seconds) increase in maximum walking time (P < .001). Relative to placebo, ramipril improved the WIQ median distance score by 13.8 (Hodges-Lehmann 95% CI, 12.2-15.5), speed score by 13.3 (95% CI, 11.9-15.2), and stair climbing score by 25.2 (95% CI, 25.1-29.4) (P < .001 for all). The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges-Lehmann 95% CI, 3.6-11.4; P = .02) in the ramipril group relative to placebo. Ramipril did not affect the overall SF-36 median Mental Component Summary score.
CONCLUSIONS AND RELEVANCE:
Among patients with intermittent claudication, 24-week treatment with ramipril resulted in significant increases in pain-free and maximum treadmill walking times compared with placebo. This was associated with a significant increase in the physical functioning component of the SF-36 score.
17. Pending PURL Review Date
sECTION 2: Critical Appraisal of Validity
[to be completed by the Potential PURL Reviewer]
[to be revised by the Pending PURL Reviewer if needed]
1. Number of patients starting each arm of the study? / 106 patients were randomized to receive ramipril and 106 to receive placebo
2. Main characteristics of study patients (inclusions, exclusions, demographics, settings, etc.)? / The study was done at three hospitals in Australia. Those enrolled had to have an ankle brachial index of less than 0.90 at rest in at least one leg, history of intermittent and stable claudication for the prior six months, and a stable medication regimen for the prior six months. Those excluded had a brachial blood pressur of 160/100mmHg or greater, use of ACEI or ARB in the prior six months, potassium-sparing diuretic or potassiu supplement use in the past six months, renal failure (Cr>2.3 mg/dL), renal artery stenosis, previous coronaryor lower extremity revascularization, myocardial infarction in the prior three months, upcoming major surgery in the next year, and any condition other than PAD limiting walking ability.
The mean age was 65 years and the majority of patients were male. The average BMI was 26. Most patients had fevoropopliteal disease. About half had hypertension and one quarter had diabetes mellitus. One-third of the patients were current smokers and about 40% were former smokers. Close to half of the patients were taking anti-platelet agents or statins. A small number were taking beta blockers. The baseline pain-free walking time was over two minutes and the maximum walking time was almost four. All patients continued to receive their usual care throughout the study. All patients received life-style advice.
3. Intervention(s) being investigated? / The associations of ramipril therapy for 24 weeks on walking distance and health-related quality of life as compared with placebo
4. Comparison treatment(s), placebo, or nothing? / placebo
5. Length of follow up? Note specified end points e.g. death, cure, etc. / 6 months
6. What outcome measures are used? List all that assess effectiveness. / The primary outcomes were pain-free walking time and maximum walking time. The xecondary outcomes were symptoms and quality of life.
7. What is the effect of the intervention(s)? Include absolute risk, relative risk, NNT, CI, p-values, etc. / Ramipril was associated with a 75-second (95% CI, 60-89 seconds) incrase in mean pain-free walking time (P<.001), and a 255-second (215-295) increase in maximum walking time (P<.001). The median distance score improved by 13.8 (Hodges Lehmann 95% CI, 12.2 to 15.5), the speed score by 13.3 (H-L 95% CI, 11.9 to 15.2), and the stair climbing score by 25.2 (H-L 95% CI, 25.1 to 29.4). The physical quality of life score improved b y 8.2 (H-L 95% CI, 3.6-11.4; p=.02) but ramipril was not associated with change in the overall mental quality of life.
8. What are the adverse effects of intervention compared with no intervention? / Dizziness was reported following initiation of treament in 5.6% of patients. Persisent cough was noted by 6.6% of the patients. One patient reported chest pain and another had pronounced ST-segment depression .
9. Study addresses an appropriate and clearly focused question - select one / Well covered
Adequately addressed
Poorly addressed
Not applicable
Comments:
10. Random allocation to comparison groups / Well covered
Adequately addressed
Poorly addressed
Not applicable
Comments:
11. Concealed allocation to comparison groups / Well covered
Adequately addressed
Poorly addressed
Not applicable
Comments:
12. Subjects and investigators kept “blind” to comparison group allocation / Well covered
Adequately addressed
Poorly addressed
Not applicable
Comments:
12. Comparison groups are similar at the start of the trial / Well covered
Adequately addressed
Poorly addressed
Not applicable
Comments:
14. Were there any differences between the groups/arms of the study other than the intervention under investigation? If yes, please indicate whether the differences are a potential source of bias. / Well covered
Adequately addressed
Poorly addressed
Not applicable
Comments:
15. Were all relevant outcomes measured in a standardized, valid, and reliable way? / Well covered
Adequately addressed
Poorly addressed
Not applicable
Comments:
16. Are patient oriented outcomes included? If yes, what are they? / Patient oriented outcomes were used including time to onset of claudication pain, maximum walking time, functional capacity and quality of life.
17. What percent dropped out, and were lost to follow up? Could this bias the results? How? / Two patients withdrew for chest pain and CAD, seven were lost to follow-up for persistent cough and three lost interest. I do not think that this would bias the results as persistent cough and non-compliance are representative of typical clinical scenarios.
18. Was there an intention-to-treat analysis? If not, could this bias the results? How? / Yes.
19. If a multi-site study, are results comparable for all sites? / There was no sub-analysis by site
20. Is the funding for the trial a potential source of bias? If yes, what measures were taken to insure scientific integrity? / No, the trial was funded by national Australian medical foundations. Though the authors have worked for large pharmaceutical companies, generic ramipril is not made by any company disclosed.
21. To which patients might the findings apply? Include patients in the study and other patients to whom the findings may be generalized. / The findings are likely applicable to all patients with PAD, including women.
22. In what care settings might the findings apply, or not apply? / These findings would apply to outpatient settings.
23. To which clinicians or policy makers might the findings be relevant? / These findings would apply to primary, cardiology and vascular surgery outpatient settings as well as insurance policy makers and possibly emergency room physicians.
SECTION 3: Review of Secondary Literature
[to be completed by the Potential PURL Reviewer]
[to be revised by the Pending PURL Reviewer as needed]
Citation Instructions / For UpTo Date citations, use style modified from http://www.uptodate.com/home/help/faq/using_UTD/index.html#cite & AMA style. Always use Basow DS as editor & current year as publication year.
EXAMPLE: Auth I. Title of article. {insert author name if given, & search terms or title.} In: Basow DS, ed. UpToDate [database online]. Waltham, Mass: UpToDate; 2009. Available at: http://www.uptodate.com. {Insert dated modified if given.} Accessed February 12, 2009. {whatever date PPRF reviewer did their search.}
For DynaMed, use the following style:
Depression: treatment {insert search terms or title}. In: DynaMed [database online]. Available at: http://www.DynamicMedical.com. Last updated February 4, 2009. {Insert dated modified if given.} Accessed June 5, 2009.{search date}
1. DynaMed excerpts
2. DynaMed citation/access date / Title. Peripheral arterial disease (PAD) of lower extremities Author. DynaMed editor In: DynaMed [database online]. Available at: www.DynamicMedical.com Last updated: Updated 2013 Mar 04 07:02:00 AM. Accessed 2013 Mar 12
3. Bottom line recommendation or summary of evidence from DynaMed
(1-2 sentences) / Angiotensin-converting enzyme (ACE) inhibitors should be considered for cardiovascular risk reduction (ACC/AHA Class IIa, Level B if symptomatic, ACC/AHA Class IIb, Level C if asymtpomatic).
4. UpToDate excerpts
5. UpToDate citation/access date / Always use Basow DS as editor & current year as publication year.
Title. Medical management of claudicationAuthor. Emile R Mohler, III, MD In: UpToDate [database online]. Available at: http://www.uptodate.com. Last updated: Jun 4, 2012. AccessedMarch 12, 2013
6. Bottom line recommendation or summary of evidence from UpToDate
(1-2 sentences) / ACEIs are not yet recommended for claudication treatment as it is considered investigational.
7. PEPID PCP excerpts
www.pepidonline.com
username: fpinauthor
pw: pepidpcp / 1. Drug therapy
oAspirin 160-325 mg qD
Recommended for pts with peripheral arterial dz
Not shown to reduce symptoms
oClopidogrel 75 mg PO qD
Used with aspirin to reduce CV risk, but not shown to reduce symptoms
oCilostazol 100 mg PO BID
FDA approved for IC
Decreases platelet aggregation
oPentoxifylline 400 mg PO BID or TID
FDA approved for IC
Increases deformability of red blood cells
oGinkgo biloba 120-240 mg/d PO div BID or TID
Dietary supplement with anti-platelet, vasodilating & antioxidant properties
Found effective at reducing symptoms in placebo-controlled trials
8. PEPID citation/access data / Author. Title. Intermittent claudication In: PEPID [database online]. Available at: http://www.pepidonline.com. Last updated: . AccessedMarch 12, 2013
9. PEPID content updating / 1. Do you recommend thatPEPID getupdated on this topic?
Yes, there is important evidence or recommendationsthat are missing
No, this topic is current, accurateand up to date.
If yes, which PEPID Topic, Title(s):
2. Is there an EBM Inquiry (HelpDesk Answers and Clinical Inquiries) as indicated by the EB icon () that should be updated on the basis of the review?
Yes, there is important evidence or recommendationsthat are missing
No, this topic is current, accurateand up to date.
If yes, which Evidence Based Inquiry(HelpDesk Answer or Clinical Inquiry), Title(s):
10. Other excerpts (USPSTF; other guidelines; etc.) / Class IIa
The use of angiotensin-converting enzyme inhibitors
is reasonable for symptomatic patients with lower
extremity PAD to reduce the risk of adverse cardiovascular
events. (Level of Evidence: B)ACC/AHA.
There is no mention of ACEIs in the 2011 update
11. Citations for other excerpts / 2005 Practice Guidelines for the Management of
Patients With Peripheral Arterial Disease (Lower Extremity,
Renal, Mesenteric, and Abdominal Aortic)
A collaborative Report from the American Association for Vascular
Surgery/Society for Vascular Surgery,* Society for Cardiovascular Angiography
and Interventions, Society for Vascular Medicine and Biology, Society of
Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines
12. Bottom line recommendation or summary of evidence from Other Sources (1-2 sentences) / Recommendations for treatment for lower extremity PAD include smoking cessation, and antiplatelet and antithrombotic drugs.
SECTION 4: Conclusions
[to be completed by the Potential PURL Reviewer]
[to be revised by the Pending PURL Reviewer as needed]
1. Validity: How well does the study minimize sources of internal bias and maximize internal validity? / Give one number on a scale of 1 to 7
(1=extremely well; 4=neutral; 7=extremely poorly)
1 2 3 4 5 6 7
2. If 4.1 was coded as 4, 5, 6, or 7, please describe the potential bias and how it could affect the study results. Specifically, what is the likely direction in which potential sources of internal bias might affect the results?
3. Relevance: Are the results of this study generalizable to and relevant to the health care needs of patients cared for by “full scope” family physicians? / Give one number on a scale of 1 to 7
(1=extremely well; 4=neutral; 7=extremely poorly)
1 2 3 4 5 6 7
4. If 4.3 was coded as 4, 5, 6, or 7, lease provide an explanation.
5. Practice changing potential: If the findings of the study are both valid and relevant, does the practice that would be based on these findings represent a change from current practice? / Give one number on a scale of 1 to 7
(1=definitely a change from current practice; 4=uncertain; 7=definitely not a change from current practice)