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Research Prioritization Topic Briefs
Topics 1-6
PCORI Scientific Program Area:
Assessment of Prevention, Diagnosis, and Treatment Options
The Johns Hopkins Evidence Based Practice Center
January 2014
This report was prepared by the Johns Hopkins Evidence Based Practice Center under the direction of the
Center for Outcomes and Evidence at the Agency for Healthcare Research and Quality. All statements,
findings and conclusions in this publication are solely those of the authors and do not necessarily
represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of
Governors. This publication was developed through a contract to support PCORI’s work and is being made
available free of charge for the information of the scientific community and general public as part of
PCORI’s ongoing research programs.
Questions or comments may be sent to PCORI at [email protected] or by mail to Suite 900, 1828 L Street,
NW, Washington, DC 20036.
Contents
Topic 1: “Treatment Options for Hypercholesterolemia” ............................................................................................. 3
Topic 2: “Treatment Options for Psoriasis”......................................................................................................................11
Topic 3: “Management of Arrhythmogenic Right Ventricular Dysplasia (ARVD)” ...........................................20
Topic 4: “Treatment Options for Pemphigus Vulgaris” ...............................................................................................24
Topic 5: “Treatment Options Involving Mesh for Management of Inguinal and Abdominal Hernias” .....32
Topic 6: “Assessment of Benefits and Harms of Pelvic Floor Mesh Implants” ...................................................40
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
2
Topic 1: “Treatment Options for Hypercholesterolemia”
Comparative effectiveness of treatment options for hypercholesterolemia among
patients who do not tolerate statin therapy
Criteria
Brief Description
Introduction
Overview/definition DESCRIPTION OF CONDITION
of topic
• Statins are effective in reducing low-density lipoprotein cholesterol (LDL-c) and preventing
cardiovascular events, however, some people cannot tolerate statin therapy due to its
adverse effects.1
• Among adverse effects reported by patients on statins, muscle toxicity, including myopathy
and rhabdomyolysis, is most definitively statin related.2 The definition of muscle toxicity
varies from study to study. We provide below commonly used definition for myopathy
and rhabdomyolysis.
o
Myopathy is defined as muscle pain or weakness with blood creatine kinases (CK) levels
more than ten times the upper limit of the normal range.3 Myopathy should not be
confused with myalgia, which refers to muscle pain without increased CK level to
greater than ten times the upper limit of normal.
o
•
•
Rhabdomyolysis is a more severe form of myopathy, with myogloblin release into the
circulation and sometimes renal failure. Rhabdomyolysis is usually diagnosed when
CK level is greater than 40 times the upper limit of normal and/or there is
evidence of end organ damage such as renal failure.
Several other adverse effects including elevated transaminases and development of
Type II diabetes mellitus are being reported in the literature;
o Mild elevation of hepatic enzymes has been reported but the cardiovascular
benefit has been proved greater than the hepatic risk. Serious
hepatotoxicity(hepatitis/liver failure) has been reported in numbers very similar
to those in the general population.4,5
The definition for “statin intolerance” varies from study to study, and there is no established
consensus: it may refer to patients who have reported statin intolerance symptoms but
who may ultimately tolerate some form of statins, or patients who are truly statin
intolerant.
•
Carefully clinical assessment, evaluation of muscle symptoms, CK level and vitamin D level
testing, along with liver, renal and thyroid function testing, and stepping down or
discontinuing current statin therapy can help to establish the diagnosis.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
3
Relevance to
patient-centered
outcomes
SYMPTOMS
• Patients usually present with muscle discomfort, soreness, tenderness, pain, or weakness
with or without CK elevations.
PATIENT-CENTERED OUTCOMES
• Mortality
• Cardiovascular events
• Muscle pain
Burden on Society
Recent prevalence
in populations
and
subpopulations
Effects on patients’
quality of life,
productivity,
functional
capacity,
mortality, use of
health care
services
PREVALENCE3
• 31.9 million adults (15% of the U.S population) have hypercholesterolemia,6 of whom 68% get
treatment. Statins are the first line treatment7,8 after dietary changes.
• In clinical studies, the rate of any adverse events has been reported as high as 5% to 10% in
randomized, placebo controlled trials, and 20% in observational studies.9-11 Up to 5% of
patients discontinue statins due to drug-related adverse events.10,11 3%–10% of patients
present myalgia(non-specific muscular aches and pains), which does not necessarily mean
statin intolerance and usually does not require discontinuing treatment.
• Statin intolerance:9,10
o Myopathy occurs in about 0.08% to 0.1% of statin users.
o Rhabdomyolysis occurs in about 0.002% of statin users.
o A higher prevalence has been observed in patients with Asian ethnicity.
o Statin intolerance may be related to patient factors such as associated conditions
(diabetes, chronic kidney disease), receiving concomitant medications, and in the
elderly.10
o Statin intolerance may be dose related.
•
•
•
•
•
Statins’ role reducing vascular disease risk has been proved.1,3 However their side effects
reduce patients’ adherence, therefore limit their benefit.4
Rhabdomyolysis is the most severe adverse event but also rare, with an estimated mortality
risk of less than 1 death per million patients.3
There seems to be an increased risk of type 2 diabetes with statin therapy, usually among
those with glucose intolerance already; however the data suggests the benefits in
cardiovascular disease risk reduction outweigh the minor worsening in glucose homeostasis.12
Even if it is recognized that adverse events can be limiting, there is no data regarding impact
on daily life.
We did not identify any data for this criterion for the alternative treatment options.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
4
How strongly does
this overall
societal burden
suggest that CER
on alternative
approaches to
this problem
should be given
high priority?
Treatment with statin therapy reduces the risk of major vascular events by approximately 21% per
1 mmol/L reduction in LDL-C, irrespective of baseline LDL-C values or history of vascular disease.
Even in lower risk individuals with less than 10% 5-year predicted risk, statin therapy translates to
an absolute reduction in major vascular events of 11 per 1000 over 5 years of treatment per 1
mmol/L LDL-C reduction. This benefit exceeds any known harms of statin therapy.13 Therefore it
is imperative that at-risk individuals be treated for cardiovascular prevention. As such, statins are
among the most prescribed drugs in the world, but unfortunately up to 5% of patients discontinue
statins due to drug-related adverse events. Muscular adverse events that are truly related to
statin therapy occur relatively rarely and a majority of patients could ultimately tolerate some
form of statins. Approaches to step down statin therapy seem to be a priority in this patient
population. In patients who are truly statin intolerant, drugs that pre-date statins and newer
agents may play a role.
Options for Addressing the Issue
Based on recent
• We did not identify any systematic reviews.
systematic
• We identified 6 completed randomized controlled trials (RCTs) that evaluated different
reviews, what is
treatment options in patients who cannot tolerate statins. All 6 trials selected lipid levels
known about the
as the main outcome and the evaluation of clinical endpoints or patient-centered
relative benefits
outcomes is extremely limited.
and harms of the
o AMG145 (a PCSK9 inhibitor) at 3 different doses vs. AMG145 plus ezetimibe vs. ezetimibe
available
plus placebo. 1 RCT (160 patients) at low risk of bias.14
management
 AMG145 was more effective than placebo/ezetimibe in reducing LDL-c level; the
options?
reduction in LDL-c was dose-dependent.
o
o
o
 AMG145 was well tolerated by patients.
Mipomersen vs. placebo. 1 RCT (33 patients) at moderate risk of bias.15
 Mipomersen was more effective than placebo in reducing LDL-c level.
 Persistent liver transaminase increases occurred in 33% (7/22) patients in the
mipomersen group.
Red yeast rice vs. red yeast rice plus placebo vs. therapeutic lifestyle program plus red
yeast rice plus placebo vs. therapeutic lifestyle program plus red yeast rice plus
phytosterol. I RCT (187 patients) at moderate risk of bias.16
 Red yeast rice improved lipid levels.
 Addition of phytosterol tablets to red yeast rice did not result in further reduction in
LDL-C levels.
 Participants in the lifestyle change program lost significantly more weight and were
more likely to achieve an LDL-C <100 mg/dL compared with usual care.
Rosuvastatin 5 mg once weekly for 8 weeks vs. placebo. 1 RCT (17 patients) at high risk of
bias.17
 Rosuvastatin was more effective than placebo in reducing LDL-c level.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
5
Two of the 17 patients (11.8%) in the placebo treatment phase and three of the 15
patients (20%) in the rosuvastatin treatment phase experienced myalgias requiring
cessation of therapy.
o Red yeast rice vs. pravastatin 20 mg twice daily for 12 weeks. 1 RCT (43 patients) at low
risk of bias18
 Red yeast rice achieved a comparable reduction of LCL-c level compared with
pravastatin
 Red yeast rice was tolerated by patients.
The 2012 Canadian Cardiovascular Society Guidelines recommended that
o Despite concerns about possible adverse effects, all purported statin-associated
symptoms should be evaluated systematically, incorporating observation during
cessation, re-initiation to identify a tolerated, statin-based therapy for chronic use; and
statins not be withheld on the basis of a potential, small risk of new-onset diabetes
mellitus emerging during long-term therapy (strong recommendation, very low-quality
evidence).
o Vitamin, mineral, or supplement use for myalgia thought to be statin-associated is not
recommended. (strong recommendation, very low-quality evidence).19
Other management considerations include using alternate lipid lowering drugs that have
previously shown to be effective based on older studies conferred in the pre-statin area.
o FDA has given niacin and bile acid sequestrations (BAS) an official indication for
regression of atherosclerosis. Although there is risk reduction of hard clinical

•
•
outcomes demonstrated by RCTs individually for niacin and BAS, there are
limitations for these agents as well. In addition, RCTs on niacin and BAS were
conducted in a in a different historical time when other contemporary
cardiovascular disease management practices were not in play. Their usefulness
when added to current preventive therapies is uncertain.
What could new
research
contribute to
achieving better
patient-centered
outcomes?
•
A universal definition of statin intolerance for use in research and in clinical practice for
comparison across studies. There are two main patient groups: one in which some form
of statin may still be used and one in which non-statin therapy must be sought.
Studies on “statin intolerance” must consider this and make the definitions explicit in
the eligibility criteria.
•
•
Better identification of risk factors for statin intolerance, perhaps genetic profiling, to
facilitate patient-specific tailored therapy.
In patients who have statin intolerance signs or symptoms, the comparative impact on the
lipid level and statin tolerability of switching to a different statin versus lowering statin dose
versus intermittent dosing (rather than daily).
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
6
•
In patients who are truly statin intolerant, the comparative effectiveness of various non-statin
therapies (ezetemibe, fibrates, and niacin) and newer agents (PCSK9 inhibitors, etc.) in
lowering lipid level and in reducing cardiovascular events.
Have recent
innovations made
research on this
topic especially
compelling?
•
Ongoing trials have compared newer agents against placebo, reduced statin therapy, dietary
supplements, or lifestyle and exercise program. The definition for statin intolerance varies
from study to study. Most of these trials selected lipids level as the primary outcome, and
very few planned to examine hard clinical endpoints such as mortality, cardiovascular events,
quality of life, or statin tolerability.
How widely does
care now vary?
•
What is the pace of
other research on
this topic (as
indicated by
recent
publications and
ongoing trials)?
The National Lipid Association Statin Safety Assessment Task Force, and the American College
of Cardiology/American Heart Association/National Heart, Lung and Blood Institute Clinical
Advisory have recommendations regarding how to manage the muscle symptoms and
appropriate use of statins.1,3,20
• We did not identify any US-based clinical practice guidelines recommending approaches to
manage patients who are truly statin intolerant. Care varies for this patient population.
ClinicalTrials.gov:
• Ongoing trials: 9
o ETC-1002 vs. placebo: 1 ongoing trial (NCT01751984)
o ETC-1002 vs. ETC-1002 plus ezetimibe: 1 ongoing trial (NCT00941836)
o Ezetimibe vs. nutraceuticals: 2 ongoing trials (NCT01490229; NCT01807078)
o Ezetimibe vs. rosuvastatin vs.: 1 ongoing trial (NCT00972829)
o Ezetimibe vs. AMG145: 1 ongoing trial (NCT01763905)
o Ezetimibe vs. atorvastatin vs. alirocumab: 1 ongoing trial (NCT01709513)
o Atorvastatin vs. PPD10558: 1 ongoing trial (NCT01279590)
o Red yeast rice vs. change of heart program: 1 ongoing trial (NTC00405769)
• It is likely that new CER on this topic would provide better information to guide clinical
decision-making. This is a very common problem in clinical practice, and there is no
consensus currently about how best to manage these statin intolerant patients.
How likely it is that
new CER on this
topic would
provide better
information to
guide clinical
decision making?
Potential for New Information to Improve Care and Patient-Centered Outcomes
What are the
FACILITATORS:
facilitators and
• Statins are among the most prescribed drugs in the world because of their established effects
barriers that
in reducing vascular disease risk.
would affect the
• Most statin intolerance symptoms are self reported and a majority of patients could
implementation
ultimately tolerate some form of statins.
of new findings in • Drugs predating statins and newer agents may play a role in patients who are truly statin
practice?
intolerant.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
7
How likely is it that
the results of new
research on this
topic would be
implemented in
practice right
away?
Would new
information from
CER on this topic
remain current
for several years?
BARRIERS:
• No established consensus on the definition of statin intolerance.
• No FDA approved drugs for statin intolerant patients and new agents are being tested in early
phase studies.
• Need a large sample size and a long follow-up time to demonstrate effectiveness on the hard
endpoints (mortality and cardiovascular events).
• In patients who have reported statin intolerance symptoms (but who may ultimately tolerate
some form of statins), a management approach based on CER is likely to be implemented due
to the lack of standard of care and large practice variations.
• In patients who are truly statin intolerant, newer agents are unlikely to be implemented
quickly because these medications would need FDA approval.
•
•
In patients who have reported statin intolerance symptoms (but who may ultimately tolerate
some form of statins), new information from CER is likely to remain current for several years
given the observed paucity of research in this field
In patients who are truly statin intolerant, depending on the results from pivotal trials, the
newer agents may (or may not) be replaced by subsequent drugs or prior-statin drugs.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
8
References for Topic 1: Comparative effectiveness of treatment options for hypercholesterolemia among patients who
do not tolerate statin therapy
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National
Lipid Association Statin Safety Assessment Task Force. The American journal of cardiology. Apr 17
2006;97(8A):89C-94C.
Armitage J. The safety of statins in clinical practice. Lancet. Nov 24 2007;370(9601):1781-1790.
Pasternak RC, Smith SC, Jr., Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory
on the use and safety of statins. Journal of the American College of Cardiology. Aug 7 2002;40(3):567-572.
Arca M, Pigna G. Treating statin-intolerant patients. Diabetes, metabolic syndrome and obesity : targets and
therapy. 2011;4:155-166.
FDA. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed Oct 18/2013.
Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics--2013 update: a
report from the American Heart Association. Circulation. Jan 1 2013;127(1):143-152.
Ford ES, Li C, Pearson WS, Zhao G, Mokdad AH. Trends in hypercholesterolemia, treatment and control among
United States adults. International journal of cardiology. Apr 15 2010;140(2):226-235.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol
Education Program Adult Treatment Panel III Guidelines. Journal of the American College of Cardiology. Aug 4
2004;44(3):720-732.
Fletcher B, Berra K, Ades P, et al. Managing abnormal blood lipids: a collaborative approach. Circulation. Nov 15
2005;112(20):3184-3209.
Vandenberg BF, Robinson J. Management of the patient with statin intolerance. Current atherosclerosis reports.
Jan 2010;12(1):48-57.
Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland
Clinic experience. American heart journal. Sep 2013;166(3):597-603.
Colbert JD, Stone JA. Statin use and the risk of incident diabetes mellitus: a review of the literature. The
Canadian journal of cardiology. Sep-Oct 2012;28(5):581-589.
Cholesterol Treatment Trialists C. The effects of lowering LDL cholesterol with statin therapy in people at low
risk of vascular disease: meta-analysis of individual data from 27 randomised trials. The Lancet.
2012;380(9841):581-590.
Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein
cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA : the journal of the American
Medical Association. Dec 19 2012;308(23):2497-2506.
Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density
lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled
trial. European heart journal. May 2012;33(9):1142-1149.
Becker DJ, French B, Morris PB, Silvent E, Gordon RY. Phytosterols, red yeast rice, and lifestyle changes instead
of statins: a randomized, double-blinded, placebo-controlled trial. American heart journal. Jul 2013;166(1):187196.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
9
17.
18.
19.
20.
Kennedy SP, Barnas GP, Schmidt MJ, Glisczinski MS, Paniagua AC. Efficacy and tolerability of once-weekly
rosuvastatin in patients with previous statin intolerance. Journal of clinical lipidology. Jul-Aug 2011;5(4):308-315.
Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20
mg twice daily) in patients with previous statin intolerance. The American journal of cardiology. Jan 15
2010;105(2):198-204.
Anderson TJ, Gregoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the
diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. The Canadian
journal of cardiology. Feb 2013;29(2):151-167.
Eckel RH. Approach to the patient who is intolerant of statin therapy. The Journal of clinical endocrinology and
metabolism. May 2010;95(5):2015-2022.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
10
Topic 2: “Treatment Options for Psoriasis”
Comparative effectiveness of treatment options for psoriasis
Criteria
Brief Description
Introduction
Overview/definition • Psoriasis is an immune related disease that causes skin cells to build up on the surface of the
of topic
skin forming itchy scaly dry red patches that can be painful. The patches can crack open and
bleed.
• The most common form of psoriasis is plaque psoriasis which is also called psoriasis vulgaris.
Over 90% of people with psoriasis have plaque psoriasis. Lesions often appear on the scalp,
trunk, limbs, nails, palms and soles of the feet.
• Psoriasis is treated with topical, oral, intramuscular, and intravenous medications as well as
phototherapy. Medications include corticosteroids, immunosuppressives, biologics and
complementary and alternative medicines.
Images of plaque psoriasis.
Relevance to
patient-centered
outcomes
Photos courtesy of dermatlas.org. All rights reserved.
SYMPTOMS
• Psoriasis lesions can be confined to small areas or widespread. Psoriasis that is widespread
and has many active lesions is considered severe and has the greatest effects on quality of
life.
PATIENT-CENTERED OUTCOMES
• Physical appearance
• Quality of life
• Risk of other immune-related disorders and tumors
• Diabetes and cardiovascular disease
• Arthritis
• Depression
• Side effects of medications
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
11
Burden on Society
Recent prevalence
in populations
and
subpopulations
Effects on patients’
quality of life,
productivity,
functional
capacity,
mortality, use of
health care
services
•
•
•
•
•
•
•
•
•
•
Psoriasis affects 7.5 million Americans1 and 2-3% of the population worldwide 2
People are most often diagnosed between the ages of 15 and 253
Men and women are equally affected3
Psoriasis varies by race with the highest prevalence among whites. 1
Children of patients with psoriasis have up to 10% chance of having the disease. 1
Most people with psoriasis will never be hospitalized for direct complications of psoriasis. In
2011, there were 118,147 hospitalizations associated with psoriasis or psoriatic arthropathy.4
Psoriasis carries a higher risk of mortality due to comorbidities such as cardiovascular disease
and diabetes as well as side effects of treatment.5-7
Psoriasis affects everyday life in about 40% of patients, and in severe cases, it negatively
impacts quality of life both physically (e.g., pain, skin manifestations of the disease,
comorbidities) and emotionally (e.g., self-consciousness, anger, frustration, helplessness). 1,8
Absenteeism is very frequent with 60% of patients with psoriasis missing 26 work days or
more per year. In severe cases more than 10% of patients are unemployed. 1,8
Almost 50% of the patients report noncompliance with treatments available, due to adverse
events or ineffectiveness.9
Psoriasis is a common autoimmune disease with numerous treatment options. These
treatments have been compared to placebo and to each other in trials, for efficacy, and
observational studies, for safety.
How strongly does
•
this overall
societal burden
suggest that CER
on alternative
approaches to
this problem
should be given
high priority?
Options for Addressing the Issue
Based on recent
• A 2012 comparative effectiveness review funded by the Agency for Healthcare Research and
systematic
Quality (AHRQ)10 included randomized controlled trials and observational studies that
reviews, what is
compared treatment with Food and Drug Administration-approved biologic systemic agents
known about the
with either an approved non-biologic systemic agent or phototherapy in adult patients with
relative benefits
chronic plaque psoriasis. Studies comparing medication with placebo were not included.
and harms of the
Outcomes of interest included body surface area affected, patient and physician assessment
available
of global improvement and individual symptom improvement, health related quality of life
management
and other patient-reported outcomes, hepatotoxicity, nephrotoxicity, hematologic toxicity,
options?
metabolic parameters (e.g., glucose, lipids, weight, body mass index and thyroid function),
hypertension, major cardiovascular events, diabetes, psychological comorbidities (e.g.,
depression and suicide), injection site reactions, malignancy, infections, study withdrawal and
mortality. Factors that modified the relationship between therapy and response were also
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
12
•
examined including age, gender, race, weight, smoking status, psoriasis severity, presence or
absence of concomitant psoriatic arthritis, disease duration, baseline disease severity,
affected body surface area, disease location, number and type of previous treatments, failure
of previous treatments and presence of neutralizing antibodies.
o Five trials and four observational studies compared therapies directly. Five studies
reported on outcomes following change in treatment to a different therapy. The studies
reported outcomes at a median of 24 weeks in small (<200 subjects) populations. Only
one study included patients from the United States.
o Four comparisons were observed, each comparing a biologic to a non-biologic agent. The
comparisons were:
 Adalimumab versus methotrexate (3 trials, 1 observational study)
 Infliximab versus methotrexate (1 trial, 1 observational study)
 Ustekinumab versus methotrexate (1 observational study)
 Etanercept versus acitretin (3 trials)
o The observed outcomes included body surface area affected (7 studies), physician global
assessment (4 studies), health related quality of life (3 studies), patient assessment (1
study), pain (1 study), pruritus (1 study) and infection (1 study).
o One modifying factor comparison met the inclusion criteria. One of the adalimumab
trials found that as disease severity improved so did health related quality of life.
o The authors concluded that there was insufficient evidence to determine comparative
effectiveness given the few therapies compared. For the four observed comparisons
they stated that there is low strength of evidence favoring the biologic.
The systematic reviews identified in the Cochrane library focused on specific types of psoriasis
or specific treatments for psoriasis.
o Topical treatments for chronic plaque psoriasis (177 randomized controlled trials,
including 26 trials of scalp psoriasis and 6 trials of inverse psoriasis or facial psoriasis;
34,808 participants): Corticosteroids and vitamin D analogues are effective with
corticosteroids associated with fewer local adverse events, although there is a lack of
evidence about the risk of skin dermal atrophy with long-term use of corticosteroids.11
o Narrow-band ultraviolet B phototherapy versus broad-band ultraviolet B or psoralenultraviolet A photochemotherapy for chronic plaque psoriasis, guttate psoriasis (small,
drop-like spotted lesions) and palmoplantar psoriasis (13 randomized controlled trials;
662 patients): Inconsistent results.12
o Interventions for chronic palmoplantar pustulosis (23 trials; 724 patients): Efficacious
treatments included systemic retinoids, oral psoralen and UVA light therapy (PUVA),
combination of PUVA and retinoids, topical steroid under hydrocolloid occlusion, low
dose ciclosporine, tetracycline antibiotics and Grenz Ray Therapy. Topical PUVA and
hydroxycarbamide (hydroxyurea) are not efficacious. Colchicine may be efficacious but
had many side effects.13
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
13
o
o
o
What could new
research
contribute to
achieving better
patient-centered
outcomes?
•
•
•
•
Have recent
innovations made
research on this
topic especially
compelling?
•
•
How widely does
care now vary?
Interventions for guttate psoriasis (1 trial; 21 patients): Intravenous infusion of an n-3
fatty acid rich lipid emulsion had some benefit compared with an emulsion containing n6 fatty acids.14
Antistreptococcal interventions for guttate and chronic plaque psoriasis (1 randomized
controlled trial; 20 patients most of whom had guttate psoriasis): No difference between
rifampicin or placebo administered at the end of a standard course of the
antistreptococcal antibiotics phenoxymethylpenicillin or erythromycin.15
Interventions for nail psoriasis (18 randomized controlled trials; 1,266 patients):
Infliximab, golimumab, superficial radiotherapy, grenz rays, and electron beam caused
significant nail improvement.16
The gaps identified from the AHRQ comparative effectiveness review are currently being
addressed by 3 R01s (1K24AR064310-01, 5R01HL089744-05, 1R01HS021589-01A1). These
R01s are examining all medication classes for short and long term outcomes, especially
cardiovascular disease, diabetes and safety.
Understanding the most important outcome measures according to patients is needed. After
patients have identified the most important outcomes, trials and observational studies can be
examined to see if they have addressed these outcomes or if additional studies are needed.
Trials registered in ClinicalTrials.gov that did not result in peer reviewed publications should
be considered.
Adherence to treatments can be an issue, especially when disease is in remission.
Understanding why patients choose to stop taking medications and developing treatment
algorithms that take into account their preferences are needed.
Environmental risk factors, such as smoking, may affect the risk and severity of disease.
Understanding the role these factors play in disease activity may be a pathway to affect
disease activity in the absence of prescription treatments.
New biologic treatments using monoclonal antibodies such as adalimumab, etanercept,
infliximab and ustekinumab have been approved by the FDA to treat psoriasis. Observational
studies based on large databases are underway to compare these treatments with each other
and older strategies such as corticosteroids combined with immunosuppressive agents and
phototherapy (1K24AR064310-01, 5R01HL089744-05, 1R01HS021589-01A1).
The out of pocket costs, including insurance co-pays, and time to receive these new
treatments should be measured as these factors affect patients.
•
•
No studies measuring variation in care in the United States were identified.
Practice variation between countries exists based on those participating in a psoriasis registry
including Australia, Denmark, Germany, Israel, Italy, Netherlands and Spain.17
•
Practice guidelines suggest different treatments for different levels of disease
severity.18
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
14
What is the pace of
other research on
this topic (as
indicated by
recent
publications and
ongoing trials)?
ClinicalTrials.gov
• 814 entries included psoriasis as a term. 744 appear to include patients with some form of
psoriasis including psoriatic arthritis.
• Interventional studies (603 entries)
o 19 are not yet recruiting
o 4 are enrolling by invitation
o 99 are recruiting
o 51 active, not recruiting
o 387 are completed (76 with results)
o 28 were terminated (13 with results)
o 10 withdrawn (none with results)
o 5 are suspended (none with results)
• Observational studies (142 entries)
o 7 not yet recruiting
o 6 enrolling by invitation
o 44 recruiting
o 20 active, not recruiting
o 57 completed (16 with results)
o 5 terminated (1 with results)
o 2 withdrawn (no results)
o 1 suspended (no results)
NIH Reporter
• 202 funded projects list psoriasis in the project terms. Eleven involve treatments of humans
with psoriasis.
o 5R01HL111293-02: Trial of TNF inhibitors, skin-directed therapy with ultraviolet B (UVB)
phototherapy and placebo on cardiometabolic disease as measured by imaging and
biomarkers.
o 5R01AR059086-04: Trial of vitamin D to prevent autoimmune diseases, such as psoriasis.
o 1K24AR064310-01 examines risk of diabetes and if adalimumab affects risk.
o 5R01HL089744-05 examines risk of myocardial infarction.
o 1R01HS021589-01A1 examines risk of diabetes and cardiovascular disease by different
treatment strategies.
o 1ZIAAR041106-18 possibly involves humans and treatment tofacitinib.
o 1R43TR000573-01: continues to build a self-assessment tool for patients with psoriasis.
o 5R21AT004966-03 examines effects of delphinidin, an antioxidant in fruit and vegetables,
in mice.
o 5R01AR059742-04 examines effects of delphinidin in skin substitutes and mice.
o 1R43AR062935-01A1 examines effects of SBD.073, a retinoid compound from plants, in
skin substitutes and mice.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
15
o
•
How likely it is that
new CER on this
topic would
provide better
information to
guide clinical
decision making?
1I01BX000706-01A2 examines effects UV therapy and TNFa inhibitors on collagen in
mice.
Cochrane Review protocols are available for methotrexate,19 ustekinumab20 and oral fumaric
acid esters21 for psoriasis, topical treatments for scalp psoriasis22 and anti-TNF agents for
pediatric psoriasis.23
•
Although there have been numerous trials and observational studies, there are few direct
comparisons of medications.
• The direct comparisons that have been made examine outcomes that may not be of interest
to the patient in the setting of trials or safety outcomes in the setting of observational study.
Understanding how medications compare when examined for outcomes identified by the
patient as important are needed.
• The majority of trials were funded by pharmaceutical companies. Conducting studies of
effectiveness and safety among investigators without conflicts is needed.
Potential for New Information to Improve Care and Patient-Centered Outcomes
What are the
FACILITATORS:
facilitators and
• New treatments such as biologics have been available to patients for a sufficient duration of
barriers that
time that non-randomized studies that assess effectiveness are possible. Studies funded by
would affect the
the National Institutes of Health are underway.
implementation
of new findings in BARRIERS:
practice?
• All patient important outcomes may not be available in existing resources to conduct the
effectiveness research. Although some patient important outcomes, such as hospitalizations,
adverse events, co-payments and time spent undergoing infusions and phototherapy
treatments, may be available.
• The majority of trials registered on ClinicalTrials.gov did not result in publications and did not
have trial results posted. Publishing results of trials, including the absence of treatment
efficacy, is needed to understand the true benefits and harms of treatments.
How likely is it that • Many health care providers prescribe based on the results of trials for efficacy and not
the results of new
comparative effectiveness research. Most of the existing treatments have been
research on this
studied in trials. Only of if there is clear superiority of a medication in terms of
topic would be
disease severity, cost or another important outcome from comparative effectiveness
implemented in
research will the results affect clinical practices. Comparative effectiveness research
practice right
should have sufficient statistical power to demonstrate clinically meaningful results
away?
for patient important outcomes.
•
If strong environmental risk factors are found for psoriasis, health care providers may choose
to inform patients about environmental modifications to reduce disease symptoms.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
16
Would new
information from
CER on this topic
remain current
for several years?
•
Monoclonal antibody based treatments are the newest strategies. Comparative effectiveness
research will remain current for several years.
•
Information on risk factors for psoriasis is likely to remain relevant for several years.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
17
References for Topic 2: Comparative effectiveness of treatment options for psoriasis
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
NPF. National Psoariasis Foundation. 2013; http://www.psoriasis.org/learn_statistics. Accessed November 12,
2013.
Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of
incidence and prevalence. The Journal of investigative dermatology. Feb 2013;133(2):377-385.
Yeung H, Takeshita J, Mehta NN, et al. Psoriasis severity and the prevalence of major medical comorbidity: a
population-based study. JAMA dermatology (Chicago, Ill.). Oct 1 2013;149(10):1173-1179.
AHRQ. http://hcupnet.ahrq.gov/HCUPnet.jsp.
Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major adverse cardiovascular events: a systematic
review and meta-analysis of observational studies. Journal of the American Heart Association. Apr
2013;2(2):e000062.
Armstrong AW, Harskamp CT, Armstrong EJ. Psoriasis and the risk of diabetes mellitus: a systematic review and
meta-analysis. JAMA dermatology (Chicago, Ill.). Jan 2013;149(1):84-91.
Dauden E, Castaneda S, Suarez C, et al. Clinical practice guideline for an integrated approach to comorbidity in
patients with psoriasis. Journal of the European Academy of Dermatology and Venereology : JEADV. Nov
2013;27(11):1387-1404.
Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity impairment among psoriasis
patients: findings from the National Psoriasis Foundation survey data 2003-2011. PloS one. 2012;7(12):e52935.
Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl MG. Undertreatment, treatment trends, and treatment
dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the
national psoriasis foundation surveys, 2003-2011. JAMA dermatology (Chicago, Ill.). Oct 1 2013;149(10):11801185.
Lee S, Coleman CI, Limone B, et al. Biologic and Nonbiologic Systemic Agents and Phototherapy for Treatment of
Chronic Plaque Psoriasis. Comparative Effectiveness Review No. 85. (Prepared by the University of
Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-200710067-I.) AHRQ Publication No.12(13)-EHC144-EF. Vol AHRQ Publication No.12(13)-EHC144. Rockville MD:
Agency for Healthcare Research and Quality; 2012.
Chalmers RJ, Hollis S, Leonardi-Bee J, Griffiths CE, Marsland AM. Interventions for chronic palmoplantar
pustulosis. The Cochrane database of systematic reviews. 2006;CD001433(2).
Chen X, Yang M, Cheng Y, Liu GJ, Zhang M. Narrow-band ultraviolet B phototherapy versus broad-band
ultraviolet B or psoralen-ultraviolet A photochemotherapy for psoriasis. The Cochrane database of systematic
reviews. 2013;10:CD009481.
Marsland AM, Chalmers RJ, Hollis S, Leonardi-Bee J, Griffiths CE. Interventions for chronic palmoplantar
pustulosis. The Cochrane database of systematic reviews. 2006(1):CD001433.
Chalmers RJ, O'Sullivan T, Owen CM, Griffiths CE. Interventions for guttate psoriasis. The Cochrane database of
systematic reviews. 2000(2):CD001213.
Owen CM, Chalmers RJ, O'Sullivan T, Griffiths CE. Antistreptococcal interventions for guttate and chronic plaque
psoriasis. The Cochrane database of systematic reviews. 2000(2):CD001976.
de Vries AC, Bogaards NA, Hooft L, et al. Interventions for nail psoriasis. The Cochrane database of systematic
reviews. 2013;1:CD007633.
Garcia-Doval I, Rustenbach SJ, Stern R, et al. Systemic psoriasis therapy shows high between-country variation: a
sign of unwarranted variation? Cross-sectional analysis of baseline data from the PSONET registries. The British
journal of dermatology. Sep 2013;169(3):710-714.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
18
18.
19.
20.
21.
22.
23.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic
arthritis: Section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: Case-based
presentations and evidence-based conclusions. Journal of the American Academy of Dermatology.
2011;65(1):137-174.
da Silva Carolina AP, Von Kossel K, Leszczynski M, Melnik T, Riera R. Methotrexate for psoriasis. Cochrane
Database of Systematic Reviews. 2013(4).
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010498/abstract.
Roberts C, Angus Janet E, Williams Hywel C, Villanueva E, Saeterdal I, Jobling R. Ustekinumab for plaque
psoriasis. Cochrane Database of Systematic Reviews. 2013(7).
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008947.pub2/abstract.
Atwan A, Abbott R, Kelly Mark J, et al. Oral fumaric acid esters for psoriasis. Cochrane Database of Systematic
Reviews. 2013(4). http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010497/abstract.
Jales Regina D, Nast A, Saconato H, Atallah Álvaro N, Hirata Sergio H. Topical treatments for scalp psoriasis.
Cochrane Database of Systematic Reviews. 2012(4).
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009687/abstract.
Sanclemente G, Murphy R, Contreras J, Rengifo-Pardo M, García H, Bonfill Cosp X. Anti-TNF agents for paediatric
psoriasis. Cochrane Database of Systematic Reviews. 2012(8).
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010017/abstract.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
19
Topic 3: “Management of Arrhythmogenic Right Ventricular Dysplasia (ARVD)”
Management of Arrhythmogenic Right Ventricular Dysplasia (ARVD)
Criteria
Brief Description
Introduction
Overview/definition DESCRIPTION OF CONDITION
of topic
• Arrhythmogenic Right Ventricular Dysplasia (ARVD) is a rare familial disorder in which the
heart muscle of the right ventricle is replaced by fibrofatty tissues. 1
• ARVD is caused by mutation in genes that encode desmosomal proteins and is usually
inherited in an autosomal dominant pattern. 1
Relevance to
SYMPTOMS
patient-centered
• A majority of affected individuals present with syncope (i.e., fainting or a sudden loss of
outcomes
consciousness) or sudden ventricular arrhythmias. These symptoms are often exerciserelated, making ARVD a leading cause of sudden death in young athletes and young adults.2
• Diagnosis of ARVD is complex but can by established by carefully following the 2010 ARVD
Diagnostic Task Force criteria, which incorporate structural, histological, electrocardiographic,
arrhythmic, and familial features of the disease.3
PATIENT-CENTERED OUTCOMES
• Arrhythmic death
• Recurrence of ventricular arrhythmia
• Occurrence of implantable cardioverter defibrillator (ICD) shock
• Quality of life
• Health care utilization
Burden on Society
Recent prevalence
in populations
and
subpopulations
Effects on patients’
quality of life,
productivity,
functional
capacity,
•
•
•
•
•
•
•
•
•
The prevalence of ARVD is between 1:1000 to 1:5000.4,5
ARVD is present in up to 20% of patients who die of sudden cardiac death (SCD), especially in
young athletes. 6
80% of the cases are teens and young adults.
A higher prevalence has been observed in Europe (Italy-Greece); in the U.S., a higher
prevalence has been observed in Caucasians.7
A family history can be found in 30-50% of the cases.5,8
A gene mutation can be found in 70-80% of cases. 7,9,10
The most studied gene has a penetrance of about 90%.4,9,11
Due to the high risk of arrhythmia and sudden death, patients are treated with ICD and
medications, however, the treatment is not always effective and the risk of recurrence is
high.12
Living with an ICD contributes to anxiety, depression and limitations in daily living activities,
which reduces quality of life and impacts health status.13
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
20
mortality, use of
• When a person is diagnosed with ARVD, his/her whole family undergoes genetic screening,
health care
which may increase the psychological burden on the family.10,14
services
How strongly does
• Although ARVD significantly impact the patients’ quality of life and the outcome can be fatal,
this overall
ARVD is a rare condition.
societal burden
suggest that CER
on alternative
approaches to
this problem
should be given
high priority?
Options for Addressing the Issue
Based on recent
• We did not identify any systematic reviews or completed randomized controlled trials (RCTs)
systematic
that assessed different treatment options for ARVD.
reviews, what is
• Most of the recommendations on management are based on clinical expertise, analysis of
known about the
observational data including patient registries, as well as an understanding of the pathologic
relative benefits
mechanisms of disease.15
and harms of the • Benefits of existing treatment options for ARVD are largely unclear due to a lack of RCT
available
evidence. Presently,
management
o ICD is the standard management.
options?
o Antiarrhythmic drugs and catheter ablation are used to decrease the frequency of
ventricular arrhythmia.
What could new
• Improved diagnosis of ARVD in primary care and local settings.
research
• Understanding of long-term course of the condition.
contribute to
• Approaches to care for women with ARVD wishing to become pregnant.
achieving better
• The comparative effectiveness of ICD vs. catheter ablation as the initial treatment for ARVD.
patient-centered • In patients with ICDs, the comparative effectiveness of antiarrhythmic drugs vs. catheter
outcomes?
ablation.
•
Have recent
innovations made
research on this
topic especially
compelling?
How widely does
care now vary?
•
•
Approaches to counsel patients and their family to improve coping with the condition and to
improve quality of life.
There is a paucity of ongoing research and innovations on this topic.
Care is very variable depending upon the experience of the cardiologist or electrophysiologist.
Patients are not routinely advised about limiting exercise. Catheter ablation for arrhythmia
management is not advised if the center has no experience with this.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
21
What is the pace of
other research on
this topic (as
indicated by
recent
publications and
ongoing trials)?
ClinicalTrials.gov:
• Ongoing trials: 1
o Standard ablation procedure (i.e., endocardial ablation only) vs. endocardial and
epicardial ablation: 1 ongoing trial (NCT01767220). The applicability of this trial to ARVD
patients is limited because ARVD patients are only a subgroup of all eligible patients.
How likely it is that • It is likely that new CER on this topic, comparing treatment strategies, would provide better
new CER on this
information to guide clinical decision-making because current management
topic would
recommendations are not based on evidence from RCTs.
provide better
information to
guide clinical
decision making?
Potential for New Information to Improve Care and Patient-Centered Outcomes
What are the
FACILITATORS:
facilitators and
• Poor and fatal outcomes for patients, and significant impact on their quality of life.
barriers that
• Early diagnosis and treatment are necessary to prevent sudden death.
would affect the
• Hospital-based ARVD patient registries exist.
implementation
of new findings in BARRIERS:
practice?
• Diagnosis of ARVD is difficult and misdiagnosis (both under and over diagnosis) is likely.
How likely is it that
the results of new
research on this
topic would be
implemented in
practice right
away?
Would new
information from
CER on this topic
remain current
for several years?
•
•
Invasiveness of catheter ablation.
A management approach based on CER is likely to be implemented expediently due to the
lack of standard of care and minimal ongoing research in the field.
•
New information from CER is likely to remain current for several years given the observed
paucity of research in this field. However, recruiting sufficient number of patients into RCTs to
investigate screening, early diagnosis, and management options with long-term and patientcentered outcomes can be challenging.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
22
References forTopic 3: Management of Arrhythmogenic Right Ventricular Dysplasia (ARVD)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society
and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation.
Mar 1 1996;93(5):841-842.
Fontaine G, Fontaliran F, Hebert JL, et al. Arrhythmogenic right ventricular dysplasia. Annual review of medicine.
1999;50:17-35.
Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular
cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. Apr 6
2010;121(13):1533-1541.
Romero J, Mejia-Lopez E, Manrique C, Lucariello R. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC/D):
A Systematic Literature Review. Clinical Medicine Insights. Cardiology. 2013;7:97-114.
Basso C, Corrado D, Marcus FI, Nava A, Thiene G. Arrhythmogenic right ventricular cardiomyopathy. Lancet. Apr
11 2009;373(9671):1289-1300.
Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience.
Circulation. Dec 20 2005;112(25):3823-3832.
Kies P, Bootsma M, Bax J, Schalij MJ, van der Wall EE. Arrhythmogenic right ventricular
dysplasia/cardiomyopathy: screening, diagnosis, and treatment. Heart rhythm : the official journal of the Heart
Rhythm Society. Feb 2006;3(2):225-234.
Basso C, Bauce B, Corrado D, Thiene G. Pathophysiology of arrhythmogenic cardiomyopathy. Nature reviews.
Cardiology. Apr 2012;9(4):223-233.
Kim C, Wong J, Wen J, et al. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs.
Nature. Feb 7 2013;494(7435):105-110.
Marcus FI, Edson S, Towbin JA. Genetics of arrhythmogenic right ventricular cardiomyopathy: a practical guide
for physicians. Journal of the American College of Cardiology. May 14 2013;61(19):1945-1948.
Corrado D, Fontaine G, Marcus FI, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an
international registry. Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the
Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology
and of the Scientific Council on Cardiomyopathies of the World Heart Federation. Circulation. Mar 21
2000;101(11):E101-106.
Dalal D, Jain R, Tandri H, et al. Long-Term Efficacy of Catheter Ablation of Ventricular Tachycardia in Patients
With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Journal of the American College of
Cardiology. 2007;50(5):432-440.
James CA, Tichnell C, Murray B, Daly A, Sears SF, Calkins H. General and disease-specific psychosocial adjustment
in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy with implantable cardioverter
defibrillators: a large cohort study. Circulation. Cardiovascular genetics. Feb 1 2012;5(1):18-24.
Quarta G, Muir A, Pantazis A, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy:
impact of genetics and revised task force criteria. Circulation. Jun 14 2011;123(23):2701-2709.
James CA, Calkins H. Update on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C). Curr
Treat Options Cardiovasc Med. Aug 2013;Aug;15(4):17-35.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
23
Topic 4: “Treatment Options for Pemphigus Vulgaris”
Comparative effectiveness of treatment options for pemphigus vulgaris
Criteria
Brief Description
Introduction
Overview/definition • Pemphigus vulgaris is an autoimmune disease that causes blisters in the mouth. Most patients
of topic
also develop blisters or widespread erosions on the skin. Other mucous membranes may also
be involved. The blisters are painful and can rupture leading to open sores that become
infected.
• Pemphigus vulgaris is frequently treated with corticosteroids; immunosuppressives such as
azathioprine, cyclosporine, cyclophosphamide, methotrexate and mycophenolate mofetil;
biologic agents such as intravenous immunoglobulin, rituximab, and anti-TNF alpha agents
used in other immune-related diseases; plasmapheresis; and extracorporeal photopheresis.
Oral, topical, intravenous, and intramuscular delivery systems are used to deliver
medications. Information on the effectiveness and safety of treatments is primarily based on
case series with a few controlled trials.1-3
Image of pemphigus vulgaris affecting the skin and mouth.
Relevance to
patient-centered
outcomes
Photos courtesy of dermatlas.org. All rights reserved.
SYMPTOMS
• Pemphigus blisters in the mouth can make it difficult to eat. Blisters on the skin may be highly
visible and can be itchy. All of the blisters can be painful.
PATIENT-CENTERED OUTCOMES
• Pain
• Itchiness
• Physical appearance
• Quality of life
• Psychological effects related to disease and or its treatments, including mood changes
• Infections, including sepsis
• Risk of other immune-related disorders and benign and malignant tumors
• Side effects of medications to treat pemphigus
•
Worsened diabetes and hypertension control due to treatments
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
24
Burden on Society
Recent prevalence
in populations
and
subpopulations
Effects on patients’
quality of life,
productivity,
functional
capacity,
mortality, use of
health care
services
•
•
•
•
•
•
Pemphigus vulgaris is a rare disease. There are up to 5 cases diagnosed per million people
each year. That’s about 1,500 new pemphigus vulgaris diagnosed each year in the entire
United States. The incidence is higher among individuals of Jewish descent.4
Both men and women are affected. The average age at diagnosis is between 40 and 60 years
old. Children are rarely diagnosed with pemphigus vulgaris.5
Hospitalizations are needed if the blisters are severe and infected. There are around 500
hospitalizations for pemphigus vulgaris each year in the United States.6
Death may result from skin infection leading to bloodstream infections. Prior to the use of
corticosteroids, pemphigus vulgaris was almost uniformly fatal within a few years of
diagnosis.
Systemic infections also may occur from the immunosuppressives used to treat the disease.
Pemphigus vulgaris affects quality of life, especially in patients with many lesions, itchy lesions
and lesions in the mouth. Over 50% of patients have anxiety or depression7 based on the
experiences of about 100 patients seen at specialty centers in Italy and Tehran.8
How strongly does
• There are many treatment options available with mostly uncertain efficacy, effectiveness and
this overall
safety profiles. The outcomes from medication use for other immune-related dermatologic
societal burden
conditions are often expected for pemphigus patients, which may not be true. Testing the
suggest that CER
efficacy, safety and effectiveness of treatments among pemphigus patients will help these
on alternative
patients and their providers make better treatment decisions specific to their condition.
approaches to
• Viral infections, especially herpes, are often associated with pemphigus. Understanding the
this problem
role of potential contributing factors, such as infections and how they affect the pathogenesis
should be given
of pemphigus could lead to better treatment, or prevention, strategies.
high priority?
Options for Addressing the Issue
Based on recent
• Two systematic reviews were identified.3,9
systematic
o Randomized controlled trials published through 2010 and written in any language with
reviews, what is
pathology-confirmed pemphigus vulgaris and pemphigus foliaceus were included.
known about the
o 12 trials were included. Of the 587 patients randomized, greater than 90% had
relative benefits
pemphigus vulgaris. The quality of the majority of trials was rated as poor.
and harms of the • The trial comparisons and results:
available
o Azathioprine compared with mycophenolate mofetil among users of oral
management
methylprednisolone (33 pemphigus vulgaris patients, mean duration of follow up of 438
options?
days, not blinded): No statistically significant difference in number of lesions, steroid
dose or adverse effects.10
o Four groups were compared: prednisolone alone, prednisolone plus azathioprine,
prednisolone plus mycophenolate mofetil, and prednisolone plus intravenous
cyclophosphamide pulse therapy (120 pemphigus vulgaris patients, 1 year, not blinded).
No statistically significant difference in lesions or adverse effects. The cumulative
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
25
o
o
o
o
o
o
o
o
o
o
prednisolone dose was highest in the prednisolone alone group (p=0.008).11
Mycophenolate mofetil compared with placebo among users of corticosteroids (96
pemphigus vulgaris patients, 1 year, blinded). No statistically significant difference in
lesions, antibody levels or quality or life. The cumulative steroid dose was lower in the
mycophenolate mofetil group (p=0.03). More infections occurred in the mycophenolate
mofetil group (p=0.04).12
Intravenous dexamethasone-cyclophosphamide pulse therapy compared with oral
methylprednisolone-azathioprine therapy (16 pemphigus vulgaris patients, 2 years, not
blinded). No statistically significant differences in lesions, adverse effects or mortality.13
Intravenous dexamethasone-cyclophosphamide pulse plus daily oral cyclophosphamide
compared with intravenous cyclophosphamide pulse plus daily oral prednisolone (28
pemphigus vulgaris patients, 1 year, not blinded). No difference in lesions, antibody
levels or adverse effects.14
Three groups were compared: prednisone alone, prednisone plus cyclophosphamide
and prednisone plus cyclosporine (28 pemphigus vulgaris patients, unknown duration,
not blinded). No statistically significant difference in lesions.15
Methylprednisolone plus cyclosporine compared with methylprednisolone alone (29
pemphigus vulgaris, unknown duration, not blinded). No statistically significant
difference in lesions, adverse effects or mortality.16
Dapsone compared with placebo among users of corticosteroids (19 pemphigus vulgaris,
1 year, blinded). No statistically significant difference in steroid dose or adverse effects.
Trial indexed in ClinicalTrials.gov: NCT0042953317
Intravenous immunoglobulin compared with placebo among users of corticosteroids (40
pemphigus vulgaris patients, 85 days, blinded). Fewer lesions and lower antibody levels
in the intravenous immunoglobulin group compared with placebo (p<0.05). No
statistically significant difference in adverse effects. One patient in the intravenous
immunoglobulin group died from hepatitis C related hepatic failure compared with no
deaths in the placebo group.18
Plasma exchange plus prednisolone compared with prednisolone alone (27 pemphigus
vulgaris, 4 weeks, not blinded). No statistically significant difference in lesions. Four of
the patients receiving plasma exchange died from infections compared with no deaths
in the prednisolone alone group.19
Topical epidermal growth factor combined with silver sulfadiazine cream compared with
silver sulfadiazine cream alone among patients receiving a variety of oral treatments (20
pemphigus vulgaris patients, 9 months, blinded). Epidermal growth factor improved
time to healing (p<0.001). No statistically significant difference in adverse effects.20 47
A traditional Chinese medicine study was identified in one review but the original article
could not be identified. There was no difference between traditional Chinese medicine
and its comparison group according to the review.3
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
26
What could new
research
contribute to
achieving better
patient-centered
outcomes?
•
•
•
•
Have recent
innovations made
research on this
topic especially
compelling?
•
•
•
How widely does
care now vary?
What is the pace of
other research on
this topic (as
indicated by
recent
publications and
ongoing trials)?
•
Trials used time to no new lesions, serum antibody levels and steroid dose as primary
outcome measures. Understanding the most important outcome measures according to
patients and designing studies to measure meaningful differences in those outcomes is
needed.
Most trials and case series reported adverse effects but it is unclear if any of the trials were
designed to measure differences in adverse effects between treatment groups. Designing
trials to measure adverse effects is especially important for trials of pemphigus treatments
where the treatment adverse effects may outweigh the benefits.
Understanding the benefits of therapies alone and in combination as well as the timing of
introduction of therapies is needed.
Environmental and genetic risk factors are suspected to play a role in the initiation of disease.
Patients may be particularly interested in knowing more about these risk factors.
New biologic treatments using monoclonal antibodies such as adalimumab, infliximab and
rituximab that are approved for other immune-related conditions such as psoriasis and
rheumatoid arthritis are used in pemphigus patients. These therapies should be tested in
clinical trials compared with traditional strategies such as corticosteroids combined with
immunosuppressive agents. The only trial that was identified did not result in a peer
reviewed publication (NCT00283712).
If the new biologic agents are superior to traditional treatments in at least some patients,
then the new biologic treatments should be compared with each other.
The cost and time to receive new treatments should be measured as these factors affect
patients.
No studies measuring variation in care were identified.
ClinicalTrials.gov
• Not yet recruiting: 1
o NCT01930175: Twelve week Phase 2 trial of VAY736 compared with placebo measuring
the Pemphigus Disease Area Index as the primary outcome. Estimated enrollment of 30
with completion in 2016.
• Recruiting: 2
o NCT01920477: Up to 60 week Phase 3 trial of ofatumumab compared with placebo with
primary outcome of “time from randomization to the time of the subject's initial
reduction of prednisone/prednisolone dose to <=10 mg/day and maintained a dose <=10
mg/day with no new or nonhealing (established) lesions for >=8 weeks and maintained
the status until Week 60 will be assessed.” Estimated enrollment of 136 with completion
in 2018.
o NCT01313923: One year Phase 1 and 2 follow up of patients treated with sirolimus (also
known as rapamycin) to decrease Autoimmune Bullous Skin Disorder Intensity Score
(ABSIS) while reducing the dose of corticosteroids. Estimated enrollment of 15 with
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
27
completion in 2015.
• Completed: 6
o NCT00283712: Trial results reported on ClinicalTrials.gov in 2012 with no associated
publications. Ten percent of patients in the infliximab (n=1) and placebo (n=10) groups
had no new lesions after week 14 and decreased steroid dose at week 18. All of the
placebo patients had a treatment-related adverse event graded 3 or greater compared
with none of the infliximab patients.
o NCT00683930: Trial results published in 2010.12 No statically significant difference in the
number of new lesions and prednisone dose below 10 mg/day between mycophenolate
mofetil and placebo at 1 year.
o NCT00626678. Completed in 2010 with no associated publications. Eleven month trial of
azathioprine compared with placebo among 48 newly diagnosed patients receiving
prednisone.
o NCT00606749: Completed in 2008 with no associated publications. Sixteen week follow
up of 20 patients treated with KC706 in combination with corticosteroids or
immunosuppressives to prevent new lesions and heal existing lesions.
o NCT00135720: Completed in 2007 with no associated publications. Sixteen week trial
with 12 patients to compare etanercept with placebo to reduce active skin lesions by
50%.
o NCT00063752: Completed in 2005 with no associated publications. Unknown duration of
follow up of 15 patients with stable disease treated with PI-0824 in combination with
corticosteroids to assess unspecified safety outcomes.
• Terminated: 1
o NCT00429533: Publication in 2008 reported on the 19 recruited patients.17 The
estimated enrollment was 48. There was no statistically significant difference in the
ability to taper steroids between the patients receiving dapsone compared with placebo
after 12 months.
• Unknown: 1
o NCT00483119: Last verified in 2009 with a status of recruiting. No associated
publications. Six to 10 week Phase 2 Randomized Trial of IV Ig with or without
cyclophosphamide to change the extent and severity of disease and decrease serum
antibodies.
NIH Reporter
• 11 studies are funded that list pemphigus vulgaris in the study terms. Three studies include
humans (5R01AR061372-02, 5K01AR056378-05, 5R01AR052672-08) and two may include
humans (2R56AI049427-11, 5R01AR055695-05).
• One of these studies aims to examine the effect of rituximab on antibodies, although no
comparison group is listed (5R01AR052672-08). No other study aims to examine the efficacy
or effectiveness of treatments on patient outcomes.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
28
How likely it is that
new CER on this
topic would
provide better
information to
guide clinical
decision making?
It is likely that comparative effectiveness research on this topic will provide better information to
guide clinical decision-making.
• New treatments are available and are being used in the absence of high quality studies
• No studies on variation in care were identified despite the numerous treatment options.
Variation in care leading to different outcomes may exist.
• No United States guidelines comparing treatment strategies for pemphigus vulgaris were
identified. High quality comparative effectiveness research can provide information on
management options for patients and providers in the absence of guidelines.
Potential for New Information to Improve Care and Patient-Centered Outcomes
What are the
FACILITATORS:
facilitators and
• New treatments for pemphigus vulgaris have been developed that patients and physicians are
barriers that
interested in using if they lead to better outcomes than existing treatments. This demand can
would affect the
facilitate increased enrollment in studies.
implementation
of new findings in BARRIERS:
practice?
• Pemphigus vulgaris is a rare disease. Identifying a sufficient number of patients to power
studies of patient-important outcomes may prove challenging without combining information
through patient research networks.
• Important safety outcomes such as cancer due to long-term use of immunosuppressives may
require long periods of observation. These endpoints may be more efficiently examined in
observational studies.
• The majority of trials registered on ClinicalTrials.gov did not result in publications and did not
have trial results posted. Publishing results of trials, including the absence of treatment
efficacy, is needed to understand the true benefits and harms of treatments for pemphigus.
How likely is it that • Patients currently use treatments with little evidence to support their use. With efficient
the results of new
dissemination of study results, we would expect rapid uptake of new information to guide
research on this
practice.
topic would be
implemented in
practice right
away?
Would new
• Monoclonal antibody based treatments are the newest strategies. Comparative effectiveness
information from
research results will remain current for several years.
CER on this topic
remain current
for several years?
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
29
References for Topic 4: Comparative effectiveness of treatment options for pemphigus vulgaris
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Kasperkiewicz M, Schmidt E, Zillikens D. Current therapy of the pemphigus group. Clinics in dermatology. Jan-Feb
2012;30(1):84-94.
Kasperkiewicz M, Shimanovich I, Meier M, et al. Treatment of severe pemphigus with a combination of
immunoadsorption, rituximab, pulsed dexamethasone and azathioprine/mycophenolate mofetil: a pilot study of
23 patients. The British journal of dermatology. Jan 2012;166(1):154-160.
Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for
pemphigus vulgaris and pemphigus foliaceus. Journal of the American Academy of Dermatology. May
2011;64(5):903-908.
Pisanti S, Sharav Y, Kaufman E, Posner LN. Pemphigus vulgaris: incidence in Jews of different ethnic groups,
according to age, sex, and initial lesion. Oral surgery, oral medicine, and oral pathology. Sep 1974;38(3):382-387.
Lo Schiavo A, Ruocco E, Brancaccio G, Caccavale S, Ruocco V, Wolf R. Bullous pemphigoid: etiology,
pathogenesis, and inducing factors: facts and controversies. Clinics in dermatology. Jul-Aug 2013;31(4):391-399.
AHRQ. http://hcupnet.ahrq.gov/HCUPnet.jsp. Accessed October 24, 2013.
Ghodsi SZ, Chams-Davatchi C, Daneshpazhooh M, Valikhani M, Esmaili N. Quality of life and psychological status
of patients with pemphigus vulgaris using Dermatology Life Quality Index and General Health Questionnaires.
The Journal of dermatology. Feb 2012;39(2):141-144.
Tabolli S, Mozzetta A, Antinone V, Alfani S, Cianchini G, Abeni D. The health impact of pemphigus vulgaris and
pemphigus foliaceus assessed using the Medical Outcomes Study 36-item short form health survey
questionnaire. The British journal of dermatology. May 2008;158(5):1029-1034.
Singh S. Evidence-based treatments for pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid: a
systematic review. Indian journal of dermatology, venereology and leprology. Jul-Aug 2011;77(4):456-469.
Beissert S, Werfel T, Frieling U, et al. A comparison of oral methylprednisolone plus azathioprine or
mycophenolate mofetil for the treatment of pemphigus. Archives of dermatology. Nov 2006;142(11):1447-1454.
Chams-Davatchi C, Esmaili N, Daneshpazhooh M, et al. Randomized controlled open-label trial of four treatment
regimens for pemphigus vulgaris. Journal of the American Academy of Dermatology. Oct 2007;57(4):622-628.
Beissert S, Mimouni D, Kanwar AJ, Solomons N, Kalia V, Anhalt GJ. Treating pemphigus vulgaris with prednisone
and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial. The Journal of investigative
dermatology. Aug 2010;130(8):2041-2048.
Rose E, Wever S, Zilliken D, Linse R, Haustein UF, Brocker EB. Intravenous dexamethasone-cyclophosphamide
pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus:
results of a multicenter prospectively randomized study. Journal der Deutschen Dermatologischen Gesellschaft =
Journal of the German Society of Dermatology : JDDG. Mar 2005;3(3):200-206.
Sethy PK, Khandpur S, Sharma VK. Randomized open comparative trial of dexamethasone-cyclophosphamide
pulse and daily oral cyclophosphamide versus cyclophosphamide pulse and daily oral prednisolone in pemphigus
vulgaris. Indian journal of dermatology, venereology and leprology. Sep-Oct 2009;75(5):476-482.
Chrysomallis F, Ioannides D, Teknetzis A, Panagiotidou D, Minas A. Treatment of oral pemphigus vulgaris.
International journal of dermatology. Nov 1994;33(11):803-807.
Ioannides D, Chrysomallis F, Bystryn JC. Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the
treatment of pemphigus. Archives of dermatology. Jul 2000;136(7):868-872.
Werth VP, Fivenson D, Pandya AG, et al. Multicenter randomized, double-blind, placebo-controlled, clinical trial
of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. Archives of
dermatology. Jan 2008;144(1):25-32.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
30
18.
19.
20.
Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for
pemphigus. Journal of the American Academy of Dermatology. Apr 2009;60(4):595-603.
Guillaume JC, Roujeau JC, Morel P, et al. Controlled study of plasma exchange in pemphigus. Archives of
dermatology. Nov 1988;124(11):1659-1663.
Tabrizi MN, Chams-Davatchi C, Esmaeeli N, et al. Accelerating effects of epidermal growth factor on skin lesions
of pemphigus vulgaris: a double-blind, randomized, controlled trial. Journal of the European Academy of
Dermatology and Venereology : JEADV. Jan 2007;21(1):79-84.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
31
Topic 5: “Treatment Options Involving Mesh for Management of Inguinal and
Abdominal Hernias”
Comparative effectiveness of treatment options involving mesh for management
of inguinal and abdominal hernias
Criteria
Brief Description
Introduction
Overview/definition • Hernias occur when there is a weakness in the abdominal fascia allowing abdominal contents
of topic
to bulge out. The bulge is often painful especially when a person exerts themself, e.g., lifts a
heavy object or coughs. If the intestine bulging out loses blood supply, emergency surgery is
required.
• Hernias are caused by defects in connective tissue or a weakness in response to abdominal
pressure. The weakness can exist from birth or can happen from increases in pressure due to
obesity, exertion, conditions such as diarrhea or constipation, or persistent coughing or
sneezing. Other risk factors for hernias include poor nutrition and smoking.1
• Treatment options for hernia include watchful waiting, a supportive garment, or laparoscopic
or open surgery.
 During surgery, a layer of mesh is often used to provide support. Hernia recurrence is
less likely to occur if mesh is used. 2.
 Mesh is generally not used for pediatric hernias.

•
•
•
•
It can be difficult to separate the risks and benefits of mesh from the type of
surgery used to place the mesh.
The mesh used during surgery comes in different forms
o Synthetic mesh
 Knitted or non-knitted sheet forms
 Absorbable mesh that degrades over time as new tissue growth occurs
 Non-absorbable mesh that provides permanent reinforcement
 A combination of absorbable and non-absorbable mesh can also be used
o Biologic mesh
 Human cadaver, pig or cow intestine or skin is processed and disinfected to create
the absorbable mesh
Individuals with infected tissue usually receive animal derived mesh to decrease the risk of
reactions to the mesh.
Occasionally mesh is used for other complex abdominal operations other than hernia repair
(e.g. rectovaginal fistula repair and rectal prolapse).
Unlike mesh used for pelvic organ operations, there are no Public Health Notifications
associated with surgical mesh implanted for hernia repair.1
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
32
Inguinal hernia before and after the use of mesh.3,4
Relevance to
patient-centered
outcomes
Illustrations By D. Alexander for AHRQ Effective Health Care Program4
PATIENT-CENTERED OUTCOMES4
• Complications after surgery depends on patient factors, type of mesh used, and surgical
technique.
• Complications also increase with age, obesity, and other patient comorbidities 5
Complications of hernia repair operations
• Hernia recurrence6
o Laparoscopic 0-14%
o Open 6-30%
• Scar
• Bleeding
• Infections
• Long-term pain
• Injury to organs, blood vessels or tube that carries semen from the testicles to the penis
• Adhesion (scar tissue that sticks together)
• Obstruction (blockage of the intestines)
• Fistula (abnormal connections between the organs, blood vessels or intestines)
• Perforation (hole in tissue or organ close to the hernia)
• Seroma (fluid build-up at the surgical site)
Complications of hernia repair operations using mesh
• Adverse events associated with mesh used for hernia repair include infections, reactions to
the mesh and damage caused by the mesh as it interacts with nearby organs and blood
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
33
vessels,1 mesh migration and mesh shrinkage 7
Burden on Society
Recent prevalence
in populations
and
subpopulations
•
•
•
•
•
•
Every year there are 700,000 to 800,000 hernia repair operations in the U.S.2,8,9
Hernias are very common. The prevalence of the difference hernia types are8
o Inguinal hernias 25%
o Umbilical hernias 10-20%
o Incisional hernias (hernia occurring in a debilitated wall after abdominal surgery) 2-10%
Hernias are more frequent in men. For every 5 men with hernias, 1 woman is affected. 2,8
Up to 1 in 4 males will develop an inguinal hernia in his lifetime. 2,8
There is no difference in hernia occurrence by race or obesity status.10
The estimates of chronic pain after surgery, with or without the use of mesh, vary
widely from less than 1 to 9% of patients. Chronic pain affects patient quality of life.11
Effects on patients’
quality of life,
productivity,
• Infection is a common complication for incisional hernia repairs performed with or without
functional
mesh. Infection increases morbidity, rate of hospitalizations and costs. Incidence of infection
capacity,
ranges from 1 to 4% in laparoscopic operations to 6-10% in open operations.12
mortality, use of
• Hernia recurrence is less likely to occur if mesh is used, decreasing the need for additional
health care
operations.2
services
How strongly does
• Hernias are common, especially among men. Understanding the differences in outcomes
this overall
with different types of surgical approach, mesh, and operative technique based on the type of
societal burden
mesh are needed.
suggest that CER
• There is a significant cost difference between types of mesh. For example, the same hernia
on alternative
can potentially be repaired with a $75 polypropylene mesh or a $10,000 biologic mesh.
approaches to
this problem
should be given
high priority?
Options for Addressing the Issue
Based on recent
• A 2012 comparative effectiveness review funded by the Agency for Healthcare Research and
systematic
Quality (AHRQ) compared surgical options for inguinal hernia3 including all study designs. The
reviews, what is
objectives of the review were comprehensive and included repair of hernias in adults and
known about the
children. Resulting studies included 123 randomized trials, 2 registries and 26 studies of other
relative benefits
designs that reported on laparoscopic surgical experience. Ten percent of the studies were
and harms of the
conducted exclusively in the U.S. Many of the studies used mesh, even if mesh was not the
available
primary comparator.
management
• Questions related directly to the use of mesh
options?
o Which type of mesh to use
o Which mesh fixation method (if any) to use
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
34
32 studies comparing the following types of mesh were identified: standard
polypropylene (PP) versus low-weight PP (6 studies), standard PP versus combination
materials (17 studies), standard PP versus coated PP (6 studies), standard PP versus
three-dimensional Prolene Hernia System (2 studies), standard PP versus porcine (2
studies), combination materials versus porcine (1 study), and low-weight PP versus
combination materials (3 studies). 23 studies compared fixation methods including:
tacks or staples versus no fixation (seven studies), fibrin glue versus staples (three
studies), sutures versus tacks (three studies), sutures versus glue (seven studies), and
absorbable sutures (short or long term) versus non-absorbable sutures (one study).
Outcomes of interest included hernia recurrence, quality of life, patient satisfaction,
long-term pain, feeling of a foreign body, infection and bleeding.
 Standard PP mesh and combination materials had similar rates of recurrence. Three
types of meshes (standard PP, low-weight PP, and porcine) had approximately
equivalent rates of long-term pain.
 Tacks, staples (metal and absorbable), no fixation, sutures and glue resulted in similar
rates of recurrence. Sutures and glue had similar effects on long-term pain. Metal
staples resulted in more long term pain than fibrin glue.
There were additional questions related to the surgical approach and operative technique to
be used for hernia repair as well as the experience of the surgeon on outcomes. These factors
may play a role on outcome in combination with the use of mesh.
9 Cochrane reviews related to hernia repair were identified. 1 compared mesh versus no
mesh during open surgery for inguinal hernia.13 Twenty trials were identified. Mesh resulted
in a substantial decrease in the recurrence of hernia (50 to 75% decrease). The use of mesh
also resulted in a quicker return to work and less persistent pain than no mesh. Types of
mesh were not compared. None of the other reviews aimed to compare different types of
mesh.
o
•
•
What could new
research
contribute to
achieving better
patient-centered
outcomes?
•
Have recent
innovations made
research on this
topic especially
compelling?
•
•
•
Comparing the risks and benefits of the different types of mesh on patient-important
outcomes is needed.
o Outcomes other than recurrence and pain are especially needed.
o Understanding the variation in use of animal-derived mesh, especially for uninfected
tissue, is needed given the greater cost compared with synthetic mesh.
Understanding the role of the type of surgery approach and operative techniques in
combination with mesh are needed.
There are multiple types of mesh available to surgeons.
The mesh used for pelvic floor disorders is the same as that used for the abdominal wall.
Understanding the variation in adverse effects, especially chronic pain, after the different
types of surgery is needed.
o Anatomic location, patient factors and surgeon factors may all affect the differences in
outcomes using the same type of mesh.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
35
How widely does
care now vary?
What is the pace of
other research on
this topic (as
indicated by
recent
publications and
ongoing trials)?
•
There are no studies on practice variation. Individual surgeon preference determines type of
mesh used and type of operation in most cases.
•
Practice guidelines recommend the use of mesh for hernia repair, when possible, due
to the decreased risk of recurrence when mesh is used.
ClinicalTrials.gov
195 entries included both hernia and mesh as terms.
• Interventional studies (147 entries)
o 8 not yet recruiting
o 1 enrolling by invitation
o 54 recruiting
o 23 active, not recruiting
o 52 completed (1 with results)
o 6 terminated (0 with results)
o 1 withdrawn (no results)
o 2 suspended (no results)
• Observational studies ( 49 entries)
o 4 not yet recruiting
o 6 enrolling by invitation
o 23 recruiting
o 4 active, not recruiting
o 8 completed
o 3 terminated
o 1 suspended
NIH Reporter
• 6 funded projects list hernia and mesh in the project terms. Four are related to hernia repair.
o 1R21DK093006-01A1 will compare the efficacy, safety and cost of a permanent, synthetic
prosthetic versus a biologic prosthetic for the one-stage repair of ventral hernias in the
setting of wound contamination.
o 5R43GM100525-02 will develop an affinity-based microparticle formulation capable of
preventing or treating hernia mesh infections by locally delivering therapeutic levels of
antibiotics. It is unclear if this study involves humans or includes a comparison group.
o 5R44GM099488-04 will examine healing rates after hernia repair by using mesh
containing adipose-derived stem cells. It is unclear if this study involves humans or
includes a comparison group.
o 5R01AG034658-03 proposes an alternative to synthetic and animal-derived mesh for
abdominal wall repair that involves “engineering the microstructure, architecture, and
mechanical properties of a biomimetic or biologically derived polymer system or an
Engineered Biologic in order to improve the initial mechanical strength of the repaired
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
36
mechanically-loaded host site and provide patient specific control of tissue regeneration
at the same time without compromising the mechanical integrity of the repaired site
during the remodeling process.” This study involves guinea pigs and it is unclear if a
comparison group will be used.
Cochrane Review protocols
• There are 7 Cochrane reviews underway
o Prosthetic mesh placement for the prevention of parastomal herniation
o Mesh fixation techniques for laparoscopic inguinal hernia repair in adults
o Mesh reinforcement versus primary repair in laparoscopic paraoesophageal hernia
repairs of the hiatus
o Preservation versus elective neurectomy of the ilioinguinal nerve for open mesh inguinal
hernia surgery
o Lightweight versus heavyweight mesh for open repair of inguinal hernia
o Lightweight versus heavyweight mesh for laparoscopic repair of inguinal hernia
o Testicular perfusion and testicular volume after inguinal hernia repair
Although there have been a few trials of different surgical techniques or types of mesh, a
comprehensive study of the different combinations in U.S. populations is lacking. The numerous
different options may limit the feasibility of a randomized trial. Additionally, studies using existing
data are challenging because standard electronic medical records and billing codes often do not
include information about the type of mesh used. Primary data collection for a prospective
cohort study or registry may be required to generate CER that can inform clinical decision making.
How likely it is that
new CER on this
topic would
provide better
information to
guide clinical
decision making?
Potential for New Information to Improve Care and Patient-Centered Outcomes
What are the
FACILITATORS:
facilitators and
• The different types of mesh are available to most surgeons.
barriers that
would affect the
BARRIERS:
implementation
• The type of surgery and experience of the surgeon may interact with the type of mesh
of new findings in
selected to affect outcomes.
practice?
• There are alternative forms of mesh in development funded by NIH. If these new types of
•
•
mesh prove useful in human studies, they will need to be compared with the currently
available types of mesh before they should be widely put into practice.
Some hospitals do not have surgeons trained in laparoscopy. If laparoscopic surgery with
mesh leads to better outcomes, these hospitals would need to hire experienced laparoscopic
surgeons.
Marketing to physicians by mesh manufacturers
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
37
How likely is it that
the results of new
research on this
topic would be
implemented in
practice right
away?
Would new
information from
CER on this topic
remain current
for several years?
•
•
•
•
The different types of mesh are available for purchase by health care providers and can be
implemented into practice right away.
Some hospitals do not have surgeons trained in laparoscopy. If laparoscopic surgery leads to
better outcomes, these hospitals will need to hire experienced laparoscopic surgeons.
New meshes are being developed. Comparing currently available meshes to these new
meshes will be needed
A new surgical technique is currently being tested in pigs to pass mesh through the stomach
wall which would eliminate scars after hernia repair.14
The currently available meshes will likely remain relevant for several years while new
meshes and techniques are developed.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
38
References for Topic 5: Comparative effectiveness of treatment options for complications of mesh used to treat hernias.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
FDA. Hernia Surgical Mesh Implants2012.
Zendejas B, Ramirez T, Jones T, et al. Trends in the utilization of inguinal hernia repair techniques: a populationbased study. American journal of surgery. Mar 2012;203(3):313-317; discussion 317.
Treadwell J, Tipton K, Oyesanmi O, Sun F, Schoelles K. Surgical Options for Inguinal Hernia: Comparative
Effectiveness Review. Rockville MD2012.
AHRQ. Consumer Summary - Surgery for an Inguinal Surgery. 2013;
http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-andreports/?pageaction=displayproduct&productid=1589.
Reynvoet E, Deschepper E, Rogiers X, Troisi R, Berrevoet F. Laparoscopic ventral hernia repair: is there an
optimal mesh fixation technique? A systematic review. Langenbeck's archives of surgery / Deutsche Gesellschaft
fur Chirurgie. Oct 13 2013.
Liang MK, Berger RL, Li LT, Davila JA, Hicks SC, Kao LS. Outcomes of Laparoscopic vs Open Repair of Primary
Ventral Hernias. JAMA surgery. Sep 4 2013.
Seker D, Kulacoglu H. Long-term complications of mesh repairs for abdominal-wall hernias. Journal of long-term
effects of medical implants. 2011;21(3):205-218.
CDC. National Center for Health Statistics fast stats for epidemiology and health statistics.
Heniford BT, Walters AL, Lincourt AE, Novitsky YW, Hope WW, Kercher KW. Comparison of generic versus
specific quality-of-life scales for mesh hernia repairs. Journal of the American College of Surgeons. Apr
2008;206(4):638-644.
Sarkhosh K, Gill R, Birch D. A Systematic Review of the Association Between Obesity and Inguinal Hernias.
SAGES2012.
Hansen MB, Andersen KG, Crawford ME. Pain following the repair of an abdominal hernia. Surgery today.
2010;40(1):8-21.
Sanchez VM, Abi-Haidar YE, Itani KM. Mesh infection in ventral incisional hernia repair: incidence, contributing
factors, and treatment. Surgical infections. Jun 2011;12(3):205-210.
Scott N, Go Peter MNYH, Graham P, McCormack K, Ross Sue J, Grant Adrian M. Open Mesh versus non-Mesh for
groin hernia repair. Cochrane Database of Systematic Reviews. 2001(3).
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002197/abstract.
Earle DB, Romanelli JR, McLawhorn T, et al. Prosthetic mesh contamination during NOTES((R)) transgastric
hernia repair: a randomized controlled trial with swine explants. Hernia : the journal of hernias and abdominal
wall surgery. Dec 2012;16(6):689-695.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
39
Topic 6: “Assessment of Benefits and Harms of Pelvic Floor Mesh Implants”
Assessment of benefits and harms of pelvic floor mesh implants
Criteria
Brief Description
Introduction
Overview/definition • Pelvic floor dysfunction occurs when the muscles in the pelvic floor are excessively weak or
of topic
excessively tight or there are joint problems in the surrounding area.
• The most common types of pelvic floor dysfunction contribute to urinary incontinence, fecal
incontinence and pelvic organ prolapse.
• Types of prolapse include anterior prolapse involving the bladder (also called cystocele),
posterior prolapse involving the rectum (also called rectocele), uterine prolapse, and small
bowel prolapse which is also called vaginal vault prolapse among women who had a
hysterectomy (enterocele).
• Risk factors include pregnancy, childbirth, parity, menopause, obesity and collagen deficiency.
• Pelvic floor dysfunction can be treated with exercises, with a device to hold organs in place (a
pessary), or with surgery.
• During surgery, mesh is sometimes inserted to provide support.
The placement of mesh may be:
 Transvaginal mesh to treat pelvic organ prolapse
 Transabdominal mesh to treat pelvic organ prolapse
 Mesh sling to treat stress urinary incontinence
• Surgery may be performed by a gynecologist, urologist, urogynecologist, colorectal surgeon or
general surgeon.
• FDA public health safety communications were published in 2008 and updated in 2011 on
transvaginal placement of mesh for pelvic organ prolapse.1,2 These notifications state that the
use of surgical mesh for transvaginal repair of pelvic organ prolapse remains a serious
concern, complications of mesh are not rare and the risk may outweigh the benefits
compared with other treatment options, including other surgeries and transvaginal repair
without mesh. 1
Relevance to
SYMPTOMS
patient-centered
• Pelvic floor dysfunction results in difficulty with or loss of control during urination, fecal
outcomes
passage difficulty or incontinence, and pelvic organ prolapse. Pelvic organ prolapse is when
an organ drops and presses against or protrudes from the vagina or rectum.
• Pain
• Pressure or discomfort
PATIENT-CENTERED OUTCOMES
• Pain
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
40
Burden on Society
Recent prevalence
in populations
and
subpopulations
•
•
•
•
•
•
•
Physical appearance
Quality of life
Recurrence
Sexual satisfaction for the patient and their partner
Urinary incontinence
Urinary tract infections
Injury to the bowel or urethra
•
Pelvic floor dysfunction only affects women. Pelvic floor disorders are very common in
women older than 20 years old, with an estimated prevalence of 24%3
Pelvic Floor Disorders contribute to4
o Urinary Incontinence with an estimated prevalence of 16%
o Fecal Incontinence with an estimated prevalence of 9%
o Symptomatic Pelvic Organ Prolapse with an estimated prevalence of 3%
A woman’s lifetime risk of surgery for pelvic floor dysfunction is 11%3,5
Older women are more likely to have a pelvic floor disorder
It is unknown if pelvic floor disorders vary by race or ethnicity3
Pelvic floor dysfunction does not increase the risk of death but it limits a woman’s quality of
life.
The cost of pelvic floor disorders to the U.S. health system for ambulatory visits was $298
million in 2006, when the most recent estimate is available. Deductibles and copayments for
the same year were an additional $114 million.6
Chronic pain resulting from pelvic floor disorder can limit functional capacity and can be
disabling.
•
•
•
•
•
Effects on patients’
quality of life,
productivity,
•
functional
capacity,
mortality, use of
•
health care
services
How strongly does
• Nearly one quarter of all adult females experience pelvic floor dysfunction.
this overall
• Pelvic floor dysfunction does not limit a woman’s lifespan but can affect her quality of life.
societal burden
• Many women face the decision for or against surgery; thus, they need information on benefits
suggest that CER
and risks of surgery.
on alternative
• Informed decision making requires knowledge about the risks and benefits of mesh.
approaches to
• Given the large number of women with this condition and the optional nature of the surgery,
this problem
comparative effectiveness research on this topic should be given high priority.
should be given
high priority?
Options for Addressing the Issue
Based on recent
• One Agency for Healthcare Research and Quality AHRQ-funded review published in 2012 on
systematic
treatments for non-cyclic chronic pelvic pain noted that the prevalence of chronic pain among
reviews, what is
women who received a mesh implant needs further research.7 Research needs included:
known about the
o Understanding benefits and harms of newer procedures to treat pelvic organ prolapse
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
41
relative benefits
and harms of the
available
management
options?
•
What could new
research
contribute to
achieving better
patient-centered
outcomes?
•
Many studies focus on mesh complications that can be identified during physical exam and
not complications that are important to patients like QOL or dyspareunia. For example, a
health care provider may notice that there is mesh visible at the incision site on vaginal exam,
but the patient and her sexual partner may not notice the mesh. Unless the visible mesh
affects safety outcomes, the visibility itself may not be important to the patient.
•
•
Have recent
innovations made
research on this
topic especially
compelling?
Assessing chronic postoperative incisional pain as factor contributing to chronic pelvic
pain
o Understanding connections between surgical approaches and nervous system changes
that may perpetuate pain (e.g., damage to pelvic nerves from thermal energy)
o Understanding the role of repeat surgeries in the same location with declining benefit as
a pain source
One Cochrane review published in 2013 compared surgical options for pelvic organ prolapse8
o 56 trials that randomized 5,954 women were included. Results that included a
comparison with mesh were:
 Upper vaginal prolapse: abdominal sacral colpopexy had a higher success rate on
examination and lower reoperation rate than transvaginal polypropylene mesh in a
single trial.
 Anterior compartment prolapse: 21 trials
•
10 trials compared sewing the pelvic floor tissue together to using mesh
(absorbable, permanent or animal-derived). Not using mesh was associated
with a 1.4 to 3 times greater risk of recurrence. There was no difference in
awareness of prolapse after the surgery between treatments. There was a lack
of information on morbidity, other clinical outcomes and patient important
outcomes. Mesh erosions occur in 10% of patients; half of women with erosion
undergo a second surgery.
o
•
•
Surgical outcomes and patient-relevant outcomes that occur when no mesh is inserted need
to be measured for comparison. For example, if there is no mesh, there cannot be mesh
erosion. However, outcomes like infections, urinary or fecal incontinence, bowel injury, pain
and patient and sexual partner satisfaction can be measured regardless of the use of mesh.
These outcomes have not been measured systematically in previous studies.
Patient and provider factors may affect patient outcomes in addition to the use of mesh. This
is insufficiently understood.
There are multiple types of mesh (synthetic and animal-derived) that have not been
compared holding constant patient characteristics, provider characteristics and surgery
characteristics.
Robotic surgery is now available to perform procedures. Comparing the outcomes of
different types of mesh using different surgical techniques (including robotic surgery) is
needed.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
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How widely does
care now vary?
What is the pace of
other research on
this topic (as
indicated by
recent
publications and
ongoing trials)?
•
Use of mesh as well as different surgical techniques varies widely as there are multiple
physician specialties that perform these procedures such as gynecologists, urologists,
urogynecologists, colorectal and general surgeons.
59 interventional and 14 observational studies were identified on ClinicalTrials.gov using the
search terms pelvic and mesh.
Interventional
• 4 not yet recruiting
• 24 recruiting
• 1 enrolling by invitation (no results)
• 10 active but not recruiting (1 with results)
• 15 completed (2 with results)
• 1 suspended (no results)
• 2 terminated (no results)
• 2 withdrawn (no results)
Observational
• 1 not yet recruiting
• 7 recruiting
• 1 active not recruiting with results
• 10 completed (1 with results)
NIH Reporter
10 funded studies were identified on NIH Reporter using the search terms pelvic and mesh. 5
appear directly related to the use of mesh.
• 5U10HD069006-03 will perform a randomized trial of different meshes, create a mesh
morbidity index and biospecimen repository, and test predictors of mesh complications.
• 5U10HD054214-08 proposes a randomized trial of uterine sparing, grafted vaginal apical
suspension compared with traditional hysterectomy with native tissue suspension to
understand if it is necessary to remove the uterus to treat uterine prolapse. Specific
outcomes of interest are not reported.
• 5U10HD041267-14 is a research network to support unspecified clinical trials for pelvic floor
disorders.
• 1R21GM107882-01 will study macrophage phenotype on mesh outcome and may involve
humans
• 5R01HD061811-05 will compare mesh outcomes using non-human primates.
No Cochrane review protocols were identified.
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
43
How likely it is that • Based on systematic reviews, the use of mesh decreases recurrence of pelvic organ prolapse.
new CER on this
However, other outcomes important to patients are not known. This information would guide
topic would
clinical decision making.
provide better
information to
guide clinical
decision making?
Potential for New Information to Improve Care and Patient-Centered Outcomes
What are the
FACILITATORS:
facilitators and
• Many women are undergoing this primarily elective procedure to improve their quality of life.
barriers that
Interested women may be more involved in the treatment decision if information is available
would affect the
to them on the risks and benefits of different providers, surgeries and the use of mesh given
implementation
their personal characteristics.
of new findings in
practice?
BARRIERS:
• There is targeted advertising to participate in lawsuits for complications of pelvic surgeries
that used mesh. Fear of litigation may affect the implementation of new findings.
• Multiple specialties are performing these procedures. Creating consensus across multiple
specialties on the best technique and type of mesh to use may be more complicated than
communication among a single specialty.
How likely is it that • Involving women in the treatment decision may decrease health care providers’ fear of
the results of new
litigation. Public reporting may increase implementation as further comparative effectiveness
research on this
research is conducted. The United Kingdom initiated a program to report on outcomes for
topic would be
hospitals and surgeons for multiple surgical specialties in 2001.9
implemented in
• There is widespread availability of mesh and physicians trained in its use, so uptake of
practice right
research into practice can be swift.
away?
Would new
• Mesh is the latest technology for pelvic organ dysfunction surgeries. Comparing different
information from
types of mesh and meshless surgery by different providers, according to different patient
CER on this topic
characteristics are needed. Comparing robotic assisted and other minimally invasive surgery
remain current
with other techniques is also needed.10
for several years?
PCORI Topic Brief: Assessment of Prevention, Diagnosis, and Treatment Options
44
References for Topic 6: Assessment of benefits and harms of pelvic floor mesh implants
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
FDA. FDA Public Health Notification: Serious Complications Associated with Transvaginal Placement of Surgical
Mesh in Repair of Pelvic Organ Prolapse and Stress Urinary Incontinence. October 20, 2008;
http://www.fda.gov/medicaldevices/safety/alertsandnotices/ucm262435.htm Accessed October 31, 2013.
FDA. FDA Safety Communication: UPDATE on Serious Complications Associated with Transvaginal Placement of
Surgical Mesh for Pelvic Organ Prolapse. July 13, 2011;
http://www.fda.gov/medicaldevices/safety/alertsandnotices/ucm262435.htm. Accessed October 31, 2013.
Nygaard I, Barber MD, Burgio KL, et al. Prevalence of symptomatic pelvic floor disorders in US women. JAMA :
the journal of the American Medical Association. Sep 17 2008;300(11):1311-1316.
Erekson EA, Lopes VV, Raker CA, Sung VW. Ambulatory procedures for female pelvic floor disorders in the
United States. American Journal of Obstetrics and Gynecology. 2010;203(5):497.e491-497.e495.
Min H, Li H, Bingshu L, et al. Meta-analysis of the efficacy and safety of the application of adjuvant material in
the repair of anterior vaginal wall prolapsed. Archives of gynecology and obstetrics. May 2013;287(5):919-936.
Sung VW, Washington B, Raker CA. Costs of ambulatory care related to female pelvic floor disorders in the
United States. American Journal of Obstetrics and Gynecology. 2010;202(5):483.e481-483.e484.
Andrews J, Yunker A, Reynolds W. Noncyclic Chronic Pelvic Pain Therapies for Women: Comparative
Effectiveness.[Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012.
Maher C, Feiner B, Baessler K, Schmid C. Surgical management of pelvic organ prolapse in women. The Cochrane
database of systematic reviews. 2013;4:CD004014.
Public reporting of surgical outcomes. The Lancet. 2011;377(9772).
http://www.medicare.gov/hospitalcompare/search.html.
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