PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 7 ( 2 0 14 ) 14 4–1 51
Available online at www.sciencedirect.com
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Therapeutic Interventions for Frail Elderly Patients: Part II. Ongoing and Unpublished Randomized Trials Melissa Bendayana , Lior Bibasb, c , Michael Levib, c , Louis Mullieb , Daniel E. Formand, e , Jonathan Afilalob, c, f,⁎ a
Department of Physiology, McGill University, Montreal, Canada Department of Medicine, McGill University, Montreal, Canada c Division of Cardiology, McGill University, Montreal, Canada d Section of Geriatric Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States e Geratric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States f Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital, Montreal, Canada b
A R T I C LE I N FO
AB S T R A C T
Keywords:
There is increasing momentum to measure frailty in clinical practice given its proven value as a
Frailty
predictor of outcomes, particularly in elderly patients with cardiovascular disease. The number
Sarcopenia
of randomized clinical trials targeting frail older adults has been modest to date. Therefore, we
Randomized clinical trials
systematically searched the ClinicalTrials.gov registry in order to review the frailty intervention trials that had been actively initiated or completed but not yet published. The interventions studied were exercise training in 2 trials, nutritional supplementation in 3 trials, combined exercise plus nutritional supplementation in 5 trials, pharmaceutical agents in 5 trials, multidimensional programs in 2 trials, and home-based services in 3 trials. Their respective study designs, populations, interventions, and planned outcomes are presented in this article. © 2014 Elsevier Inc. All rights reserved.
The past 15 years have seen a sharp rise in frailty research, reflecting the need to better characterize an aging and increasingly complex population. The interest in frailty has spread from geriatric medicine to other specialties such as surgery and cardiovascular medicine,1,2 which have echoed the powerful prognostic impact of frailty. Frailty has become engrained as a geriatric vital sign, making its way into the lexicon of day-to-day clinical practice and into cardiology guideline documents.3 Sarcopenia, reflecting the variable agerelated loss of muscle mass and strength, is at the core of the frailty phenotype. Treatment strategies for frail and sarcopenic patients may consist of interventions to reverse
or delay the progression of frailty,4 as well as tailored clinical care pathways to optimize their health status and/or guide them toward less aggressive treatments. Despite the enthusiasm surrounding frailty, there has been a visible lag in published randomized clinical trials (RCT) aimed at treating frailty (Fig 1). ClinicalTrials.gov is a web-based database that catalogs up-and-coming RCTs; it currently contains >130,000 trials from more than 170 countries worldwide and is operated by the United States National Library of Medicine. Thus, the objective of this review was to provide an outline of the RCTs registered in the ClinicalTrials.gov database for the treatment of frail individuals.
Statement of Conflict of Interest: see page 150. ⁎ Address reprint requests to Jonathan Afilalo, MD, MSc, Division of Cardiology, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine Rd, E-222, Montreal, QC H3T 1E2, Canada. E-mail address: [email protected] (J. Afilalo). http://dx.doi.org/10.1016/j.pcad.2014.07.005 0033-0620/© 2014 Elsevier Inc. All rights reserved.
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 7 (2 0 1 4) 14 4–1 5 1
Abbreviations and Acronyms
Methods
CVD = cardiovascular disease The ClinicalTrials.gov registry was queried using the following PPT = physical performance test search string: (frail OR frailty OR sarcopenic RCT = randomized clinical trial OR sarcopenia) AND (randomized). The “Interventional” filter was selected. The inclusion criteria for this review were: (1) randomized controlled trial, (2) ongoing or completed but not yet published, (3) population of older adults with frailty/pre-frailty or sarcopenia as determined by an objective assessment tool (broadly defined as a multi-item frailty scale such as Fried’s,5 low muscle mass and/or strength, slow gait speed, short physical performance battery [SPPB] or other physical performance tests [PPT]), (4) intervention aimed at improving the frailty phenotype or downstream outcomes. To confirm unpublished status, PubMed and Web of Knowledge were queried for each eligible trial. Exclusion criteria were: observational studies, trials terminated prematurely, “frail” populations wherein the term was used in a subjective fashion (e.g. to denote very old individuals, those with disabilities, or those living in nursing homes), cohorts of patients post-orthopedic surgery, post-stroke, or with active cancer. The rationale for excluding orthopedic and stroke cohorts was that these patients possess specific deficits and needs for physical and occupational rehabilitation. The rationale for excluding patients with active cancer was that cancer-related cachexia is often confused with sarcopenia, yet inherently distinct in its pathobiology and treatment.6 Trial characteristics were retrieved from ClinicalTrials.gov in XML format and tabulated using a custom script written for NYHA = New York Heart Association
500 450 400 350 300 250 200 150 100 50
1987 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0
"Frail Elderly"[Mesh] "Frail Elderly"[Mesh] AND "Randomized Controlled Trial"[Publication Type]
Fig 1 – PubMed entries for frailty and frailty randomized trials by year.
145
this purpose. Supplemental information was obtained from the trial methodology papers when these were available. In addition, investigators were contacted by e-mail to clarify details relating to trial status and design if there were missing data. Eligible trials were screened by duplicate observers and disagreements about the inclusion or exclusion of a given trial were resolved by consensus. Since included trials were not published in manuscript format at the time of our search, final results were not reported.
Results The search identified 265 entries, of which 20 met the inclusion criteria for this review (Table 1, Fig 2). The official status was not yet recruiting in 5 RCTs, recruiting in 6, active but not recruiting in 4, and completed but not yet published in 5. The frailty criteria used to determine eligibility were PPTs in 8 RCTs, Fried’s scale in 6, muscle mass with or without PPTs in 3, and other scales in 3. Five RCTs focused on individuals with a specific comorbidity: stable coronary artery disease, diabetes, heart failure, chronic obstructive pulmonary disease, obesity, and osteopenia. The vast majority excluded those with recent cardiac events within 6 months, NYHA III–IV heart failure, significant dementia as measured by a minimental status examination score
Available online at www.sciencedirect.com
ScienceDirect www.onlinepcd.com
Therapeutic Interventions for Frail Elderly Patients: Part II. Ongoing and Unpublished Randomized Trials Melissa Bendayana , Lior Bibasb, c , Michael Levib, c , Louis Mullieb , Daniel E. Formand, e , Jonathan Afilalob, c, f,⁎ a
Department of Physiology, McGill University, Montreal, Canada Department of Medicine, McGill University, Montreal, Canada c Division of Cardiology, McGill University, Montreal, Canada d Section of Geriatric Cardiology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States e Geratric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States f Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital, Montreal, Canada b
A R T I C LE I N FO
AB S T R A C T
Keywords:
There is increasing momentum to measure frailty in clinical practice given its proven value as a
Frailty
predictor of outcomes, particularly in elderly patients with cardiovascular disease. The number
Sarcopenia
of randomized clinical trials targeting frail older adults has been modest to date. Therefore, we
Randomized clinical trials
systematically searched the ClinicalTrials.gov registry in order to review the frailty intervention trials that had been actively initiated or completed but not yet published. The interventions studied were exercise training in 2 trials, nutritional supplementation in 3 trials, combined exercise plus nutritional supplementation in 5 trials, pharmaceutical agents in 5 trials, multidimensional programs in 2 trials, and home-based services in 3 trials. Their respective study designs, populations, interventions, and planned outcomes are presented in this article. © 2014 Elsevier Inc. All rights reserved.
The past 15 years have seen a sharp rise in frailty research, reflecting the need to better characterize an aging and increasingly complex population. The interest in frailty has spread from geriatric medicine to other specialties such as surgery and cardiovascular medicine,1,2 which have echoed the powerful prognostic impact of frailty. Frailty has become engrained as a geriatric vital sign, making its way into the lexicon of day-to-day clinical practice and into cardiology guideline documents.3 Sarcopenia, reflecting the variable agerelated loss of muscle mass and strength, is at the core of the frailty phenotype. Treatment strategies for frail and sarcopenic patients may consist of interventions to reverse
or delay the progression of frailty,4 as well as tailored clinical care pathways to optimize their health status and/or guide them toward less aggressive treatments. Despite the enthusiasm surrounding frailty, there has been a visible lag in published randomized clinical trials (RCT) aimed at treating frailty (Fig 1). ClinicalTrials.gov is a web-based database that catalogs up-and-coming RCTs; it currently contains >130,000 trials from more than 170 countries worldwide and is operated by the United States National Library of Medicine. Thus, the objective of this review was to provide an outline of the RCTs registered in the ClinicalTrials.gov database for the treatment of frail individuals.
Statement of Conflict of Interest: see page 150. ⁎ Address reprint requests to Jonathan Afilalo, MD, MSc, Division of Cardiology, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine Rd, E-222, Montreal, QC H3T 1E2, Canada. E-mail address: [email protected] (J. Afilalo). http://dx.doi.org/10.1016/j.pcad.2014.07.005 0033-0620/© 2014 Elsevier Inc. All rights reserved.
PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S 5 7 (2 0 1 4) 14 4–1 5 1
Abbreviations and Acronyms
Methods
CVD = cardiovascular disease The ClinicalTrials.gov registry was queried using the following PPT = physical performance test search string: (frail OR frailty OR sarcopenic RCT = randomized clinical trial OR sarcopenia) AND (randomized). The “Interventional” filter was selected. The inclusion criteria for this review were: (1) randomized controlled trial, (2) ongoing or completed but not yet published, (3) population of older adults with frailty/pre-frailty or sarcopenia as determined by an objective assessment tool (broadly defined as a multi-item frailty scale such as Fried’s,5 low muscle mass and/or strength, slow gait speed, short physical performance battery [SPPB] or other physical performance tests [PPT]), (4) intervention aimed at improving the frailty phenotype or downstream outcomes. To confirm unpublished status, PubMed and Web of Knowledge were queried for each eligible trial. Exclusion criteria were: observational studies, trials terminated prematurely, “frail” populations wherein the term was used in a subjective fashion (e.g. to denote very old individuals, those with disabilities, or those living in nursing homes), cohorts of patients post-orthopedic surgery, post-stroke, or with active cancer. The rationale for excluding orthopedic and stroke cohorts was that these patients possess specific deficits and needs for physical and occupational rehabilitation. The rationale for excluding patients with active cancer was that cancer-related cachexia is often confused with sarcopenia, yet inherently distinct in its pathobiology and treatment.6 Trial characteristics were retrieved from ClinicalTrials.gov in XML format and tabulated using a custom script written for NYHA = New York Heart Association
500 450 400 350 300 250 200 150 100 50
1987 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
0
"Frail Elderly"[Mesh] "Frail Elderly"[Mesh] AND "Randomized Controlled Trial"[Publication Type]
Fig 1 – PubMed entries for frailty and frailty randomized trials by year.
145
this purpose. Supplemental information was obtained from the trial methodology papers when these were available. In addition, investigators were contacted by e-mail to clarify details relating to trial status and design if there were missing data. Eligible trials were screened by duplicate observers and disagreements about the inclusion or exclusion of a given trial were resolved by consensus. Since included trials were not published in manuscript format at the time of our search, final results were not reported.
Results The search identified 265 entries, of which 20 met the inclusion criteria for this review (Table 1, Fig 2). The official status was not yet recruiting in 5 RCTs, recruiting in 6, active but not recruiting in 4, and completed but not yet published in 5. The frailty criteria used to determine eligibility were PPTs in 8 RCTs, Fried’s scale in 6, muscle mass with or without PPTs in 3, and other scales in 3. Five RCTs focused on individuals with a specific comorbidity: stable coronary artery disease, diabetes, heart failure, chronic obstructive pulmonary disease, obesity, and osteopenia. The vast majority excluded those with recent cardiac events within 6 months, NYHA III–IV heart failure, significant dementia as measured by a minimental status examination score
