June 12th, 2011

CardioExchange Panel: Whither High-Dose Simvastatin?

Last week, the FDA issued a warning high-dose simvastatin because of the risk of myopathy.

CardioExchange got the reactions from a panel we assembled. Whose views do you agree with? What points did our panelists miss?

See a similar panel’s reactions the publication of the SHARP Trial here.

Given the FDA warning, do you see any role for high-dose simvastatin? 

Steven E. Nissen, MD

I wrote a JAMA editorial about high-dose statins in ACS back in 2004. The FDA should have removed simvastatin 80 mg from the market years ago.

Allen Taylor, MD

The FDA statement is consistent with a clinically-relevant safety difference that has been recognized for some time now- particularly important among the elderly with reduced renal function and those on certain concomitant therapies. Given numerous safe therapeutic alternatives for high potency statins, I believe simvastatin at the 80 mg/d dose should be avoided. I disagree with the FDA statement from the perspective of whether patients currently taking the 80 mg dose should continue on that dose. I personally favor conversion of any patient taking the 80 mg dose to an alternative treatment approach (different statin or simvastatin dose reduction), to avoid problems from interactions with future concomitant therapies, or changes in the rate of drug clearance.

Sanjay Kaul, MD

I stopped using high-dose simvastatin many years ago because of heightened risk of myopathy. I substitute 20-40 mg atorvastatin or 10-20 mg rosuvastatin for patients requiring greater than 40 mg simvastatin. In general, I am not a big fan of initiating high-dose statin therapy, even for patients with ACS. I like to start with low to intermediate statin dose and titrate up to optimize adherence. The adverse event rates related to statins is much higher in the real world practice compared with randomized trials where most patients intolerant to statins are filtered out during the active treatment “run-in” phase prior to randomization.

The concerns have been seen in clinical trials since the A to Z study was published in JAMA in 2004. At least 2 recent reports from the SEARCH study confirmed the risk. Also, simvastatin is cleared by cytochrome P 450 3A4, and many commonly used medications inhibit this pathway, so it is rather easy for patients on this high dose of simvastatin to develop “supra-therapeutic” blood levels of the drug. Of note, attempts at developing the 160 mg dose of simvastatin for clinical use were derailed because of muscle problems.

James H. Stein, MD

This is an especially important report because simvastatin is the most commonly used generic statin in the US and its rate of use still is rising. A lot of patients were put on 80 mg of simvastatin when it went generic or are put on it after MIs, and it, quite simply, is not as safe as high dose atorvastatin or rosuvastatin.

3 Responses to “CardioExchange Panel: Whither High-Dose Simvastatin?”

  1. William DeMedio, MD says:

    I believe that with the proper monitoring, high dose simvastatin can be safe enough and effective enough to be used in a subset of patients who cannot afford the newer, safer, agents. It is true of all statins that the higher the dose, the greater the risk of myopathy. Simvastatin has more years of use than any of its newer competitors, and this alone should give confidence to the FDA to condone its use. The FDA seems not to mind leaving the 2,000,000 Americans already on simvastetin 80 mg alone, yet they place a major financial obstacle in front of those who cannot afford the newer agents and do not qualify for benefit programs.
    As a government regulatory agency, FDA’s fiduciary duty lies with the citizens of the United states. Their first job is to make sure the risk/benefit ratio of meds is of a safe proportion. It does not have to be perfect(nothing is). The second job of FDA is to ensure the medication actually does what it is supposed to do. Simvastatin fits the bill.
    With informed discussion in the Patient/Doctor encounter and proper patient monitoring 80 mg simvastatin can be safely used. The choice to use it should be reserved for the patient after consultation with their doctor.
    I fear that what will become of this FDA decision is the following: people will stop using simvastatin and take nothing. In CAD a statin is better than no statin. We will see a spike in CVD deaths in a few years.
    The same thing happened with SSRI’s in teens and young adults a few years ago. Doctors and patients’ became afraid to use them because of the percieved threats in suicidality. But when you you look at the M&M data the actual suicide rate doubled when the meds were discontinued or not prescribed first line. Things are finally returning to normal. The suicide rates in teens are down because of appropriate treatment.
    FDA makes some very interesting snap decisions. A few drugs that was grandfathered in as safe and effective years ago and have proven themselves with the test of time suddenly had to pass FDA muster (L thyroxine and colchicine are examples). FDA suddenly wants the manufacturers to submit NDA equivalents or face having their low cost, safe, effective drugs from the market. The new colchicine costs my patients 100 times what the old formulations cost and only works just as well. FDA collects a substantial fee for these NDA’s and a good number of the people on the FDA board have industry conflicts of interest. This comes off the backs of my gout patients who cannot afford the new formulation and must now suffer because we have already determined colchicine works best for them.
    One of my patients with a long list if allergies and osteoarthritis and Migraine dropped by last week. I asked her how she was doing? Answer: terrible. Asked her why? Because the only thing that ever gave her pain relief and did not make her sick was propoxyphene. The FDA took it off the market some months mack.
    When I look at my old Geneva Conventions card it says something about care for the sick and wounded and relief of pain and suffering. It does not say look at statistics and follow the commands of your leaders regarding medical care. This is precisely what FDA is now doing, they sit in a government office and collect fees from manufacturers to follow the statistics and dictate what they believe is safe and effective using data and computers. In fact they should spend some time on the front of the war on illness and see what impact their decisions have on those who matter most, our patients. I am now fielding calls from people who want to know if their simvastatin is safe rather than taking care of the sick. What is The FDA thinking?

    Competing interests pertaining specifically to this post, comment, or both:
    I Pay Taxes.

  2. Leon Hyman, Ms M.D. says:

    If it is not broken don’t fix it. If someone is tolerating 80 mg of Simvastatin then leave them alone. This is completely different then starting them on the drug for the first time. If they require more than 40 mg of simvastatin, then going to atorvastatin or rosuvastatin is safer. The exception would be a patient who can’t afford the brand names. Then a full discussion of the risk of the increased dose of simvastatin is obviously indicated.

    Competing interests pertaining specifically to this post, comment, or both:

  3. David Powell , MD, FACC says:

    I have not used simva 80 since A to Z. My only surprise is the amlodipe issue. Was this based on soley pharmacodynamic studies? As we know from RE-LY, these short studies can overestimate chronic effects. Is there credible on treatment clinical data to support the interaction? Another comment: if the FDA wanted to be be complete and have the greatest positive impact on patient care, why not include a statement on renal function? Or did they? Even if there is nothing officially new.

    Competing interests pertaining specifically to this post, comment, or both: