Six Month (Primary) Outcomes Frequently Asked Questions

Peripheral artery disease (PAD) is blockage of the arteries in the legs. Lower extremity PAD affects more than 8 million Americans and over 27 million in North America and Europe.  As many as 10-30% of these individuals experience a discomfort, fatigue or pain in their leg muscles with exercise that quickly goes away with rest.  This leg muscle symptom is known as “claudication” and markedly worsens quality of life.

Because both PAD and the claudication symptom are so common, it is important to patients, their loved ones and families, to physicians, to health systems and to payors to define the best strategies of care (the treatment with greatest benefit and lowest risk).  CLEVER was designed to fill this need. 

 

What was the purpose and design of the study?

Answer:  CLEVER was designed to evaluate the relative benefit, harm, and cost-effectiveness of the three most common treatments used to improve leg symptoms (known as “claudication”) in patients with peripheral artery disease, or PAD.  Benefit and harm are measured at two time points:  Six and eighteen months. Cost-effectiveness will be assessed only at 18 months. 

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What were these treatments?

Answer:  One group of patients was randomly assigned to receive instruction in use of a home walking program and were asked to use an FDA-approved claudication medication called cilostazol. 

A second group of patients was randomly assigned to undergo an angioplasty and stent placement, which is a procedure that opened the blocked main artery that supplies the leg muscles.  These patients also took cilostazol.

A third group (optimal medical care or “OMC”) was asked to exercise three days a week under professional supervision for six months.  These patients also took cilostazol

Optimal medical care of risk factors for the disease was recommended to all patients.

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Did patients in each treatment group receive their assigned treatment?

Answer:  Yes. Most patients who were asked to use cilostazol at home, did so, taking over 90% of their assigned medication.  Patients who were assigned to receive a stent, underwent successful angioplasty and stent placement, successfully opening the artery.  Patients who were asked to perform exercise in a supervised (rehabilitative) setting did this with a high compliance rate as well. The CLEVER study defined “adequate compliance” up front with the exercise protocol when a patient attended 70% or more of the prescribed sessions.  In CLEVER, 71% of SE patients achieved this yardstick of compliance.

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What were the key results of CLEVER?

Answer:  Patients in both the supervised exercise and stent groups enjoyed major improvements in peak walking time (like “maximal walking distance” a treadmill test assessment of how far a patient can walk) compared to patients who were assigned to the optimal medical care (home walking and cilostazol) group.  Also, quality of life improved in both the exercise and stent groups compared to optimal medical care.  Of the three treatments offered, the group that participated in the supervised exercise intervention walked the farthest at the end of the six month treatment period. However, the stent group had the most improvement in quality of life measures.

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What most surprised you about the CLEVER results? 

Answer:  A number of past “single center” studies have compared the efficacy of supervised exercise to stent treatments.  In each of these, supervised exercise demonstrated equal or better results than stenting to improve claudication symptoms.  Thus, while CLEVER surprised many by the achievement of longer pain free walking distance on treadmill by the supervised exercise group compared to stent group, in retrospect, this may not be a real surprise.

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What are the implications for clinical practice and for patients?

Answer:  Patients with PAD and iliac artery disease have two good treatment options: supervised exercise rehabilitation or stent placement.  These two treatments are not mutually exclusive; they can be used individually or together.  More will be known about these treatment options once the 18 month results from  the trial are known.

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Why did the OMC group not improve despite their use of home exercise and an FDA-approved claudication medication?

Answer:  The OMC group did achieve a longer pain free walking distance compared to baseline, however, this was a much smaller benefit than that achieved in the other two groups.  Cilostazol is an effective claudication medication, as demonstrated in many randomized placebo-controlled trials that included thousands of patients.  A recent metanalysis (a study that combines the results of other studies) showed that 40% of patients treated with cilostazol achieved an improvement in pain free walking ability.  The improvement observed in the OMC group (20%) was not surprising given the small sample size. In addition, 15 to 20% of the individuals randomized in CLEVER were using cilostazol at baseline, and these individuals were included in the analyses when measuring changes from baseline to 6 months. Thus, CLEVER does not demonstrate the efficacy of cilostazol.  In does, however, demonstrate that both exercise and stenting can provide superior improvements in claudication symptoms at six months.

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Why did supervised exercise work so well if the artery was not opened?

Answer:  Supervised exercise has long been known to provide major improvements in leg function, even when the main arteries remain blocked, for many possible reasons. Exercise is known to improve skeletal muscle strength and efficiency by improving the tiny “cellular power plants (the mitochondria) that provide energy to working muscle.  Exercise is also known to improve the blood flow within the microscopic arteries that bring this blood into working muscles (these microscopic arteries control blood flow in all body organs).  In addition endothelial function (regulation of blood flow has been shown to be improved by exercise. These and many other mechanisms are proven to occur with exercise and have always been demonstrated to be powerful means to improve leg function. 

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Why did the stent group improve quality of life better than the exercise group?

Answer:  The answer is unknown, and CLEVER does not provide data to answer this important question. 

It is important to recognize that QOL improved greatly in both the supervised exercise group and in the stent group.  One might speculate that individuals in the stent group may have reported more improvement in quality of life measures, since the change in their symptoms was more immediate. Such immediate improvements may be more memorable, whereas the improvements that are achieved with supervised exercise are more gradual and may thus be reported less clearly. 

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How important is the improvement in HDL and fibrinogen in the exercise group?

Answer:  The current study does not define the clinical importance of these biochemical improvements enjoyed by patients who completed the supervised exercise treatment.  However, it is also clearly established that increases in HDL are usually associated with lower rates of heart attack and stroke.  Similarly, it is known that individuals with lower fibrinogen levels have less “inflammation” and also often enjoy lower heart attack and stroke rates.  These clinical benefits cannot be observed in a study with as few patients as CLEVER followed for only 6-18 months. 

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Could CLEVER help patients become more involved in their choice of PAD and claudication care?

Answer:  Yes, and this may be a major result of this landmark trial.  The CLEVER results allow patients to be more informed regarding the benefit and safety of each available claudication treatment.  CLEVER provides the best answer to the following questions:

  1. “If I have aorto-iliac PAD and claudication, what three treatments are available to me?”  (ANSWER:  Cilostazol, supervised exercise and stenting).
  2. Which of these treatments is most effective at improving my maximal walking capacity at six months?  (ANSWER: Supervised exercise best improves walking ability at six months, and does so with greater efficacy than stenting alone).
  3. Which of these treatments is most effective at improving quality of life at six months?  (ANSWER:  Stenting provides the greatest improvements in reported quality of life and this improvement, while unexplained, was greater than that of supervised exercise).
  4. What if my doctor tells me that supervised exercise is not available to me or is not reimbursed by my health insurer?  (ANSWER: Any cardiac rehabilitation or physical therapy program could provide the CLEVER exercise program.  The “recipe” for success has been published and is available to all.  If your health insurer does not provide coverage for the most effective and safe claudication treatment, you should ask your doctor to petition for such coverage).

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Were the claudication treatments safe? Did patients undergoing exercise therapy suffer an increased risk of heart attack compared to those that received a stent in the CLEVER trial?

Answer: No, there was no increased risk of heart attack, or any adverse event, in patients participating in the supervised exercise group in the CLEVER study. In fact, if exercise were sustained, it is likely that the risk of heart attack and stroke would be significantly reduced, as exercise in known to improve blood pressure, cholesterol, and diabetes.

As well, stenting was also a safe treatment.

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CLEVER FACTS

Enrollment End Date:
Total Enrollment:
Enrolling Sites:
12/31/2010
119
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