pletal
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Synonyms
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Pletal (cilostazol) is a quinolinone derivative phosphodiesterase III inhibitor with vasodilatory and antiplatelet properties, primarily indicated for symptomatic management of intermittent claudication in peripheral arterial disease. Unlike many vasodilators that primarily affect proximal vessels, Pletal’s unique mechanism targets the microcirculation while simultaneously inhibiting platelet aggregation - a dual action that made it particularly interesting when we first started working with it in our vascular clinic back in the2003.
Pletal: Evidence-Based Management of Intermittent Claudication - Comprehensive Review
1. Introduction: What is Pletal? Its Role in Modern Vascular Medicine
Pletal represents one of the few pharmacologic options specifically approved for symptomatic improvement in intermittent claudication. When patients present with that classic cramping pain in calves, thighs, or buttocks that resolves with rest, we’re dealing with Rutherford category 1-3 peripheral artery disease. What makes Pletal particularly valuable is that it doesn’t just mask symptoms - it actually improves functional capacity through multiple physiological pathways.
I remember when we first introduced it to our formulary, there was skepticism among some of the older vascular surgeons who were accustomed to either telling patients to “just live with it” or jumping straight to invasive interventions. But the data, and more importantly the patient outcomes, gradually won them over.
2. Key Components and Pharmacokinetics of Pletal
The active pharmaceutical ingredient is cilostazol, a synthetic compound with the chemical name 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone. It’s formulated in 50 mg and 100 mg tablets, with the standard maintenance dose being 100 mg twice daily.
The pharmacokinetics are particularly noteworthy - cilostazol undergoes extensive hepatic metabolism primarily via CYP3A4 and to a lesser extent CYP2C19. This creates significant drug interaction considerations that we’ll discuss later. The metabolites, particularly OPC-13015 and OPC-13213, maintain pharmacological activity, contributing to the overall therapeutic effect.
Bioavailability is approximately 90% when taken on an empty stomach, but we typically recommend taking it at least 30 minutes before or 2 hours after meals to avoid the high-fat meal effect that can increase AUC by up to 90%. The half-life is about 11-13 hours for cilostazol and significantly longer for the active metabolites, which explains the twice-daily dosing schedule.
3. Mechanism of Action: Scientific Substantiation of Pletal’s Effects
The mechanism of action involves several complementary pathways that differentiate it from other vasoactive agents. Primarily, Pletal inhibits phosphodiesterase III (PDE3), leading to increased intracellular cyclic AMP (cAMP) in platelets and vascular smooth muscle cells.
In platelets, elevated cAMP inhibits aggregation - this is the antiplatelet effect that reduces thrombotic risk in compromised vessels. In vascular smooth muscle, increased cAMP promotes vasodilation, particularly in the femoral artery bed. But here’s what many clinicians miss: Pletal also directly inhibits adenosine uptake, which potentiates endogenous adenosine-mediated vasodilation.
We’ve observed in our vascular lab that the vasodilation isn’t generalized - it’s preferentially directed toward skeletal muscle vasculature, which explains why patients experience improved walking distance rather than just systemic blood pressure changes. The drug also demonstrates mild antiproliferative effects on vascular smooth muscle cells, potentially slowing disease progression.
4. Indications for Use: What is Pletal Effective For?
Pletal for Intermittent Claudication
The primary FDA-approved indication is symptomatic improvement of intermittent claudication. In clinical practice, we typically see maximum walking distance improvements of 40-50% from baseline after 12-24 weeks of therapy. The effect isn’t immediate - patients need to understand it may take 4-12 weeks to notice significant improvement.
Pletal in Critical Limb Ischemia
While not FDA-approved for critical limb ischemia, some vascular specialists use it off-label in early-stage CLI (Rutherford category 4) as adjunctive therapy. The evidence here is more limited, but we’ve had some success in delaying progression in select patients who aren’t immediate revascularization candidates.
Pletal for Secondary Prevention
The antiplatelet effects provide secondary cardiovascular protection, though it’s not typically prescribed solely for this purpose. We occasionally use it in patients who cannot tolerate aspirin or clopidogrel but need antiplatelet therapy.
5. Instructions for Use: Dosage and Course of Administration
The standard dosage is 100 mg twice daily, taken at least 30 minutes before or 2 hours after breakfast and dinner. For patients who experience troublesome side effects (particularly headache or gastrointestinal symptoms), we sometimes initiate at 50 mg twice daily for 2-4 weeks before escalating.
| Clinical Scenario | Dosage | Frequency | Administration Timing |
|---|---|---|---|
| Standard maintenance | 100 mg | 2 times daily | 30 min before morning/evening meals |
| Initial therapy or intolerance | 50 mg | 2 times daily | Same as above |
| Hepatic impairment | 50 mg | 2 times daily | With caution and monitoring |
| CYP inhibitor coadministration | 50 mg | 2 times daily | Required adjustment |
The treatment course should continue for at least 12 weeks to assess efficacy. If no improvement in walking distance is observed by 3 months, discontinuation should be considered. For responders, we typically continue indefinitely unless contraindications develop.
6. Contraindications and Drug Interactions with Pletal
Contraindications include congestive heart failure of any severity class - this is black-box warning territory due to increased mortality observed with other PDE3 inhibitors in heart failure patients. The concern stems from positive inotropic effects potentially exacerbating underlying myocardial dysfunction.
Other important contraindications include known hypersensitivity to cilostazol, active pathological bleeding, and severe hepatic impairment.
Drug interactions are extensive due to CYP metabolism:
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin) require dose reduction to 50 mg twice daily
- CYP2C19 inhibitors (omeprazole, lansoprazole) may increase exposure
- Antiplatelet agents and anticoagulants increase bleeding risk
- Grapefruit juice should be avoided due to CYP3A4 inhibition
We had a case early on - Mr. Henderson, 68-year-old with well-controlled claudication on Pletal, was prescribed clarithromycin for pneumonia. Nobody caught the interaction, and he developed significant tachycardia and hypotension. Fortunately, it resolved with discontinuation, but it taught us to be meticulous about medication reconciliation.
7. Clinical Studies and Evidence Base Supporting Pletal
The evidence base for Pletal is substantial, with multiple randomized controlled trials demonstrating efficacy. The landmark studies include:
- The Cilostazol vs. Placebo for Intermittent Claudication (1999): 8 centers, 239 patients, showing 47% mean improvement in maximal walking distance vs 13% with placebo
- Cilostazol vs. Pentoxifylline (2000): Demonstrated superiority to pentoxifylline with 54% vs 30% improvement in walking distance
- Meta-analysis by Thompson (2002): Pooled data from 8 trials confirmed significant improvements in both pain-free and maximal walking distances
What’s particularly compelling is the quality of life data - patients report not just increased walking distance but improved ability to perform daily activities, reduced pain, and better overall wellbeing.
We participated in a registry study that followed 427 patients over 3 years. The maintenance of improved walking distance was sustained in about 65% of compliant patients, with the main reason for discontinuation being side effects rather than loss of efficacy.
8. Comparing Pletal with Similar Products and Choosing Appropriate Therapy
When comparing Pletal to alternatives, several factors distinguish it:
- vs. Pentoxifylline: Pletal demonstrates superior efficacy in head-to-head trials, though pentoxifylline may be better tolerated in some elderly patients
- vs. Naftidrofuryl: Available in Europe but not FDA-approved in US; similar efficacy profile but different mechanism
- vs. Exercise therapy: Actually, the best outcomes occur when Pletal is combined with supervised exercise therapy - they’re synergistic rather than competitive
The choice often comes down to patient-specific factors. For younger, more active patients wanting maximal functional improvement, Pletal is usually first-line. For frail elderly or those with multiple medication interactions, we might start with pentoxifylline or focus solely on exercise.
9. Frequently Asked Questions (FAQ) about Pletal
What is the typical timeframe to notice improvement with Pletal?
Most patients begin noticing increased walking distance within 4-6 weeks, with maximal benefit typically achieved by 12-16 weeks. We tell patients it’s not like nitroglycerin - the effect builds gradually.
Can Pletal be combined with other antiplatelet medications?
Yes, but with caution. We frequently use it with aspirin in appropriate cardiovascular risk patients. Dual therapy with clopidogrel requires careful bleeding risk assessment. Triple therapy (with anticoagulant) is generally avoided due to bleeding concerns.
Are the side effects of Pletal typically transient?
The most common side effects - headache, diarrhea, palpitations - often diminish after the first 2-4 weeks as patients develop tolerance. Persistent symptoms may require dose reduction or discontinuation.
Is Pletal safe in diabetic patients with peripheral artery disease?
Generally yes, and particularly beneficial since diabetes accelerates PAD progression. However, careful monitoring is needed as diabetes often coexists with renal impairment and other comorbidities that may affect dosing.
Can Pletal be used after peripheral vascular interventions?
We often continue it peri-procedurally unless there’s specific concern about bleeding. Some evidence suggests it may reduce restenosis risk, though this isn’t an approved indication.
10. Conclusion: Validity of Pletal Use in Clinical Practice
The risk-benefit profile supports Pletal as a valuable tool in comprehensive PAD management. It’s not a magic bullet - it works best as part of a multimodal approach including risk factor modification, exercise therapy, and appropriate revascularization when indicated.
I’ve been working with this medication for nearly two decades now, and what continues to impress me isn’t just the clinical trial data but the real-world impact. I’m thinking of Sarah Johnson, a 72-year-old who came to us barely able to walk to her mailbox. After 3 months on Pletal combined with our supervised exercise program, she was walking half a mile daily and had resumed gardening - something she thought she’d lost forever.
The key is patient selection and management of expectations. It doesn’t work for everyone, and the side effects can be challenging initially. But for the right patient, with proper education and monitoring, Pletal can meaningfully improve both quantity and quality of life.
We recently did 5-year follow-up on our first 100 patients started on Pletal back in 2004-2005. About 40% were still on it, with maintained functional benefits. The ones who discontinued mostly did so due to new contraindications (developing heart failure mostly) or cost issues rather than lack of efficacy. That longitudinal experience has solidified my confidence in its appropriate role in our vascular toolkit.
Clinical note: The headache issue is real - we lost about 15% of patients in the first month due to intolerable headaches. But the ones who push through often get good results. We’ve found that starting at 50mg BID for the first month then increasing helps retention. Also, the palpitations worry some patients, but they’re typically benign - just need good patient education upfront.