FPIN Journal Club
RANDOMIZED CONTROLLED TRIAL
SPEAKER NOTES
Title: Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind ,
placebo-controlled trial.
Journal Club Author: Thomas Satre, MD St. Cloud University of Minnesota/St. Cloud Hospital
Family Medicine Residency, St. Cloud, MN USA.
Journal Club Editor: Kate Rowland, MD, MS, Rush-Copley Medical Center
PURL Citation: J Fam Pract. 2015;64:182-184
Original Article: Br J Dermatol. 2014;170:1151-1157
1. What question did the study attempt to answer?
Patients – Filipinos aged 18 to 85 years with 1 or more venous ulcers for at least 3 months.
Infected wounds and wounds larger than 10 cm were excluded.
Intervention – Simvastatin 40 mg daily plus usual treatment (compression, elevation, and wound
care).
Comparison – Identical appearing placebo plus usual treatment.
Outcome – Primary outcome – proportion of patients with complete healing at 10 weeks.
Secondary outcomes – total surface area healed, healing time, and Dermatology Life Quality
Index scores.
Did the study address an appropriate and clearly focused question
Yes
No
2. Determining Relevance:
a. Did the authors study a clinically meaningful
Yes
No
and/or a patient oriented outcome?
b. The patients covered by the review similar to your population
Yes
No
This was a Filipino population with relatively low incidence of diabetes (5%).
3. Determining Validity:
Study design;
a. Was it a controlled trial?
Yes
No
b. Were patients randomly allocated to
comparison groups?
Yes
No
Unclear
c. Were groups similar at the start of a trial?
Yes
No
Unclear
Yes
No
Unclear
d. Were patients and study personnel “blind” to treatment?
e. Aside from allocated treatment, were groups treated equally?
Yes
No
Unclear
f. Were all patients who entered the trial properly accounted for at its conclusion?
Yes
No
Unclear
Five of 66 patients dropped out because of non-attendance at follow-up
appointments, 3 in the simvastatin group and 2 in the placebo group.
4. What are the results?
a. What are the overall results of the study?
Complete healing at 10 weeks:
Simvastatin group, all sizes = 90%
Placebo group, all sizes = 34%
(RR 0.16; 95% CI, 0.05-0.47; NNT=2)
Simvastatin group, ulcers < 5 cm = 100%
Placebo group, ulcers < 5 cm = 50%
(RR 0.10; 95% CI, 0.01-0.71, NNT=2)
Simvastatin group, ulcers > 5 cm = 67%
Placebo group, ulcers > 5 cm = 0%
(RR 0.33; 95% CI, 0.12-0.84, NNT=1.5)
Healing times:
Simvastatin group, all sizes = 7.53 + 1.34 weeks
Placebo group, all sizes = 8.55 + 1.13 weeks
Dermatology Life Quality Index:
Simvastatin group had statistically significant improvements compared to
placebo group (numerical results not reported).
b. Are the results statistically significant?
c. Are the results clinically significant?
d. Were there other factors that might have
affected the outcome?
5. Applying the evidence:
a. If the findings are valid and relevant, will this change
your current practice?
b. Is the change in practice something that can be done in
a medical care setting of a family physician?
c. Can the results be implemented?
d. Are there any barrier to immediate implementation?
e. How was this study funded?
Funding source reported as “none.”
Yes
Yes
No
No
Yes
No
Yes
No
Yes
Yes
Yes
No
No
No
6. Teaching Points
Absolute Risk Reduction (ARR) and Calculating a NNT
The ARR is the absolute difference between the control event rate and the experimental event
rate.
The primary event rate in this study is the proportion of healed ulcers at 10 weeks:
Simvastatin group = 90% (26 of 29 patients)
Placebo group = 34% (11 of 32 patients)
ARR = 0.90 - 0.34 = 0.56 = 56%.
The NNT is the inverse of the ARR (1/ARR) = 1/0.56 = 1.8
Since we don’t treat 0.8 of a patient, we always round NNT up to the next whole number, so the
Number Needed to Treat is 2.
34% of the patients in this study healed with placebo and usual care alone. So some patients—
about a third-- will experience an improvement in their wound with the things that we are doing
now: local wound care, bandaging, elevation. But nine of out ten got better if they took
simvastatin along with the usual care.
Therefore, you will need to treat 2 patients with simvastatin plus usual treatment for 10 weeks
to heal 1 more ulcer compared to usual treatment alone.
Using inclusion/exclusion criteria to determine relevance to one’s own practice
The inclusion criteria for this study are listed as:
“Men or women aged 18–85 years, with single or multiple ulcers confirmed by duplex scan to be
venous in origin, and who were willing to have elastic compression therapy, were recruited. The
ulcers had to have been open for at least 3 months.”
The exclusion criteria are listed as:
“Exclusion criteria included the application or intake of antibiotics or any phlebotropic or
venoactive drugs for at least 2 weeks before enrolment; large, circumferential ulcers (> 10 cm);
grossly infected lesions needing oral or intravenous antibiotics and ancillary therapy; elevated
liver enzymes or hepatic disease; renal pathology; myopathies; cataracts; compromised immune
states; or any other major medical problems that the investigator deemed to increase the risk of
adverse events with the intervention. Patients who were taking coumarin derivatives, digoxin,
fibrates or high-dose niacin, ciclosporin, nefazodone, methotrexate, verapamil, diltiazem,
angiotensin-converting enzyme inhibitors, systemic azole antifungals or systemic macrolide
antibiotics; those who were pregnant or lactating; those with known or suspected drug abuse
problems; alcoholics; or those who were unlikely to be amenable to follow-up were also
excluded.”
The exclusion criteria seem lengthy, but they are appropriate for an initial study of a new
therapy. By excluding infected ulcers and extremely large ulcers, the researchers selected a
population that would likely respond in the time frame of the study. By excluding patients with
medical conditions or medication regimens that may increase the risk of adverse events from
simvastatin, the researchers limited potential harm from their intervention. Some of these
criteria seem overly restrictive as many primary care clinicians use simvastatin for lipid-lowering
in these situations, but in the context of a trial examining simvastatin as therapy for wounds,
they make sense.
Also important to consider is the population that the patients were recruited from – a
dermatology referral population in the Philippines.
Compared to the typical primary care population in the United States, important items to
consider would be:
1. The prevalence of obesity and diabetes in the Filipino population are lower than in the
U.S. population, 2 factors that may affect ulcer healing.
2. A dermatology referral population may have different ulcer characteristics than a
primary care population.
3. The effect of simvastatin on infected wounds and wounds larger than 10 cm is
unknown.
4. Patients with medical conditions or medication regimens that may increase the risk of
adverse events with simvastatin were excluded. The benefit to risk ratio may be
different if these populations were included.
Before adopting a new treatment, it is important to compare the study population to your own.
Realize that the treatment may perform differently in different populations. The use of
simvastatin is definitely supported in patients with non-infected venous ulcerations < 10 cm and
few other comorbidities. Outside of this population, clinicians need to carefully weigh the
potential risks of simvastatin because the benefits may less.