Statins For Elderly People – A Deceptive Message

People older than 65 years are at increased risk for cardiovascular disease (CVD). Such disease accounts for more than 80 percent of deaths in this population. Age itself appears independently associated with risk, and risk factors such as high blood pressure, lipid disorders and diabetes are common among the elderly.

An important question facing the medical community is whether statin drugs can reduce risk among elderly people without established CVD. Limited clinical research is available addressing statin treatment among healthy individuals above 65 years old.

Recently a meta-analysis was published by Savarese and coworkers in the Journal of the American College of Cardiology (JACC) addressing the effects of statins in elderly subjects without established cardiovascular disease. Eight trials were included in the final analysis.

The results made the headlines and the message was quite clear. The authors concluded that their “meta-analysis provided the first-time evidence that the benefits of statins on major cardiovascular events extended to people above 65 years old”. Such a message is certainly something for authors of clinical guidelines to chew on.

In an accompanying editorial in JACC, David D. Waters, MD, wrote: “Older people differ more among themselves than younger people do in many ways, and the decision to treat or not treat an older individual with a statin often requires clinical discernment. The clear results of this meta-analysis will hopefully lead to more older individuals receiving treatment that will reduce their cardiovascular risk”.

Savarese and coworkers conclude from their meta-analysis that 24 patients need to be treated with statins for a year to prevent one heart attack (myocardial infarction) and 42 patents need to be treated for a year to prevent one stroke. However, I suspect they may have miscalculated their data. My calculation, based on data presented in the paper indicates that the number needed to treat (NNT) is approximately ten times higher. If this is true the effect of statin therapy is seriously exaggerated in the paper.

The Number Needed to Treat

The meta-analysis by Savarese and coworkers did not show a significant effect of statin treatment on mortality compared to placebo. Myocardial infarction occurred in 2.7% of subjects allocated to statins compared with 3.9% of those on placebo during a mean-follow up of 3.5 years. The absolute risk reduction during this time period is 1.2%.

The annual rate of myocardial infarction was 1.1% on placebo and 0.8 percent on statins. The absolute risk reduction in a a year is about 0.34 percent. Although the risk reduction is statistically significant, it is obvious that the number of patients needed to be treated for a year to prevent one event can not be 24.

The NNT is the inverse of the absolute risk reduction (ARR): NNT = 100/ARR.

  • If ARR is 1 percent, the NNT will be 100.
  • If ARR is 10 percent, the  NNT will be 10.
  • If ARR is 0.1 percent, the NNT will be 1.000.

Accordingly, if the absolute risk reduction is less than 1 percent, the NNT will always be above 100.

My calculation based on data from Table 2 in the paper indicates that about 234 patients need to be treated for one year to prevent one myocardial infarction, and that about 389 patients need to be treated for one year to prevent one stroke. I hope someone corrects me if I’m wrong. If I’m right, I may have a hard time understanding how such miscalculation can survive a peer-reviewed process in a respected medical journal. NNT is an important number to look at when deciding whether to give a certain treatment or not.

Studies of statins in primary and secondary prevention suggest these drugs increase the risk of diabetes. For comparison, it is estimated that 250 patients need to be treated with a statin for one case of diabetes to be caused. So by looking at the data we can assume that by treating 250 elderly people with statins for a year, we may actually exchange one myocardial infarction for one case of diabetes .

The Emperor’s New Clothes

One of the authors of the above mentioned meta-analysis, Dr. Antonio Gotto JR said in an interview following the publication of the paper: “Taking statins may not prolong life in older adults, but it may certainly improve the quality of life for people who might otherwise become disabled by heart attacks and strokes”.

Savarese and coworkers point out that statins reduce the risk of myocardial infarction by 39.4 percent and the risk of stroke by 23.8 percent compared with placebo. These are the numbers they get when calculating relative risk reduction. The results are statistically significant, certainly suggesting a positive effect of statin therapy.

However, let’s take a closer look at the magnitude of treatment effect. An individual not given statin therapy has a 98.9 percent chance of not having a heart attack, and a 99.2 percent chance of not having a stroke in a year. If given statins, the chance of not having a heart attack will be increased to 99.2 percent and the chance of not having a stroke will be increased to 99.4 percent. Not very impressive if we look at it this way.

Keep in mind when looking at these numbers that we don’t have access to data on the side effects of statins from these trials. It is possible that older people are more vulnerable to side effects than young people. There is evidence of harm linked to statins when given to elderly individuals, including muscle pain, liver disorders, impaired memory, increased risk of diabetes and gastrointestinal stress.

In my opinion, the meta-analysis by Savarese and coworkers does not provide strong support for statin treatment of elderly people with elevated cardiovascular risk. More data is needed until such marching orders are given to practicing clinicians.

Comments

    • Doc's Opinion says

      Thanks for providing the link Cassie. It’s a good general discussion about the difference between absolute and relative risk reduction which is important to understand. It doesn’t adresss the specific paper I was discussing though.

  1. Philip says

    Can anybody here advise me what is now best to do?

    I am 70 years old, had a heart attack 24 years ago and bypass surgery 11 years ago.For almost a year I have been following a low carbohydrate diet and with excellent results ,results are as follows.

    Total cholesterol 129 mg/dl
    HDL 57 mg/dl

    non HDL cholesterol 72mg/dl

    Triglycerides 91mg/dl

    Blood glucose 82 mg/dl

    All tests done after 12 hours fasting.

    Weight loss 38 Kg.

    During my recent visit to my family doctor [GP] I was advised that I could stop taking Statins [current dosage 10 mg/day Simvastatin] .I listened to the advice but mentioned that during a brief stay in hospital in August of 2013 for Atrial Fibrillation, the cardiologist told me in a very aggressive manner that I must not stop taking Statins because they help to ensure that the grafts used in the bypasses are kept open as best as possible.

    He even advised that I at least double my daily dosage to 20 mg.

    I decided to leave the dosage at 10mg/day and to see if healthy eating and moderate daily exercise would be sufficient. After all, the blood analysis measures fatty and waxy materials in the blood and not the fractions that may or may not be depositing on blood vessel walls.

    My inclination is to follow the advice of the cardiologist since he is the specialist and deals with these problems on a daily basis in a cardiology ward.

    Would appreciate any comments regarding the mixed messages I am getting from my health carers.

    Thanks in advance,

    Philip.

    • Doc's Opinion says

      Philip. Clinical trials indicate that patients with established coronary artery disease benefit from statin therapy. I agree that your lipid levels are quite low with a calculated LDL-C around 54 mg/dl. If I had a patient in a similar situation I would most probably recommend continuing with simvastatin 10 mg daily, unless there are side effects. I would probably not increase the dose. Thanks for the post.

  2. says

    Axel I believe your calculation is correct and the paper is in error. I am going to send your blog to Dr. David Newman who runs the web site theNNT.com. He is really excellent in parsing the data. I did the same calculation you did with respect to MI’s and came up with an NNT of 83.33 over 3.5 years to prevent one MI – not sure how you handle the range of years of follow up but assuming that the NNT would be about 3 times in one year what it is in three years, I agree with you that the study contains false data.

    • Doc's Opinion says

      Thanks Barbara. To get the NNT for a year you vill need to multiply by 3.5 like you say. The result will depend a little bit on which numbers are used when calculating the absolute risk reduction. The NNT for one year will be between 230-280 for MI, and between 380-420 for strokes. That is approximately 10 times higher than reported in the paper.

  3. says

    I was referring to the fact that the mean follow up was 3.5 plus or minus 1.5 years. But that is a small matter. It is hard to see how they could have miscalculated but they did.

    • Doc's Opinion says

      Barbara. I’ve been trying to figure out how they’ve done their calculations.

      Here is how I think they might have done it: They’ve calculated the NNT for 3.5 years which is 83 for MI and 143 for stroke. In order to find the NNT for one year they may have divided by 3.5. By doing that they would have arrived at numbers which are close to those reported in the paper. However, instead of dividing, they should have multiplied by 3.5.

      However, I’m surprised the authors didn’t find the low NNT numbers suspicious. They are much lower than reported NNT´s in similar studies where ARR is higher. They even mention the NNT numbers in their discussion when saying: “The cost-benefit evaluation of treatment in elderly people must also be considered. From our analysis, 24 or 42 elderly subjects without established CV disease would need to be treated with statins for 1 year to prevent 1 MI or 1 stroke, respectively”.

      Another peculiar thing is how it has escaped the attention of the reviewers as well.

  4. says

    Yesterday, the Editor-in-Chief of the Journal of the American College of Cardiology (JACC) responded to an e-mail I sent him. He acknowledges the above mentioned error in the paper by Savarese and coworkers. He also said they are moving to correct it.

    I’ll be sending a formal “letter to the editor” in hope of it being published alongside a correction of the data. I look forward to see the correct NNT (number needed to treat).

  5. Mie says

    Axel, good job in pointing out the mistake. However, this

    “In my opinion, the meta-analysis by Savarese and coworkers does not provide strong support for statin treatment of elderly people with elevated cardiovascular risk.”

    left me thinking. NNTs for statins are usually given using five-year efficacy, right? This would mean that the NNT for statins in primary prevention among the elderly within a five-year period would be around 50 for MI and 80 for strokes. And this in a population with no established CVD.

    If there is another form treatment that gives such benefits, I’d like to hear it.

    • Doc's Opinion says

      Mie. I get your point. The effect of statins in terms of NNT in this meta-analysis is probably nit very different from that seen in other studies on statins in primary prevention. For a large population of individuals you may actually prevent a number of MI´s and strokes. However, you have to be careful when you don’t have access to data on side effects or possible harms.

      I wonder why the effect on strokes and MI’s does not translate into a significant reduction in mortality. Are there harmful effects of statins that neutralize the reduction in cardiovascular events? I don’t know, just a speculation. But there certainly are side effects that influence quality of life. About 10 percent will have muscle damage and about 2 percent will develop diabetes. Compare this to the PREDIMED study (effects of a Mediterranean type diet) where the number needed to prevent one a stroke, heart attack, or death over five years was 61, with zero side effects.

      When looking at this from the perspective of the individual patient the NNT over 5 years also means that 49 out of 50 will not have an MI and 79 out of 80 will not have a stroke if they decide to not take statins. When the absolute risk is low and the absolute risk reduction small, a large proportion of patients will not derive any benefit from therapy. Considering the risk of side effects, recommending statin therapy based on these numbers becomes a bit hard in my opinion.

      • steve says

        just means you need to properly choose patient for statin treatment. I would hate to be the 1 0r 2 out of 50 who has an event cause the doc just looked at population stats.

      • Doc's Opinion says

        Steve. I totally agree. Of course clinical trial results are one of the main tools we have to guide us in the right direction. But it’s important to understand that many other factors come into play. Informing the patient about the pros and cons of pharmacologic treatment is important. That’s the role of the physician. Of course he/she also has to inform the patient about other alternatives, lifestyle issues etc. A well educated patient will be able to participate in the decision on whether to treat with statins or not.

  6. Mie says

    “About 10 percent will have muscle damage and about 2 percent will develop diabetes. Compare this to the PREDIMED study (effects of a Mediterranean type diet) where the number needed to prevent one a stroke, heart attack, or death over five years was 61, with zero side effects.”

    Axel, PREDIMED didn’t result in improvements in MI in fully adjusted analysis: the reduction in combined end points was due to improvement in the reduction of strokes. And did PREDIMED researchers even address the issue of such side effects as seen with people on statins? Not even diets are devoid of possible side effects. Plus the subjects in PREDIMED were already on statins so it really doesn’t provide us with that much insight on what happens in primary prevention setting when comparing statins and Med. diet.

    “Considering the risk of side effects, recommending statin therapy based on these numbers becomes a bit hard in my opinion.”

    Well then, what would the numbers have to be like then?

    • Doc's Opinion says

      Mie. Of course the PREDIMED study has limitations. The reason I mentioned it is because it illustrates a different approach to cardiovascular prevention. Because you mention the effect of the Mediterranean diet on MI vs. stroke in PREDIMED it is important to understand that the study was powered only for the composite end point. Thus, separating the endpoints may be problematic, but that’s a different issue.

      When looking at the effects of statins in primary prevention, the numbers speak for themselves. I’m in favor of shared decision making. When it comes to the individual patient I try to inform them as well as I can about the options. I tell them about the pros and cons of statins. I tell them the about the trials. I tell them that statins may be effective when it comes to preventing cardiovascular events. I also tell them about the side effects. I educate them about lifestyle options. I’m not against statin treatment in high risk individuals. I’m prescribing statins all the time. However, I believe the effect of these drugs for primary prevention is severely overestimated and I believe that side effects are seriously underreported.

      • Mie says

        You really didn’t answer my last question. Yes, when treating an individual patient, you obviously consider the absolute risks etc. But that wasn’t the issue here.

        “However, I believe the effect of these drugs for primary prevention is severely overestimated and I believe that side effects are seriously underreported.”

        What makes you believe so?

      • Doc's Opinion says

        Mie. On the question I did not answer I can say this: The data on the effects of statins following acute myocardial infarction are an example of “what the numbers have to be like then” for me to accept them.

        Regarding the above question: “What makes you believe so?” I’ve written a number of articles on statin therapy on my blog. I believe they will answer your question on why I believe the effect of these drugs for primary prevention is severely overestimated and I why I believe that side effects are seriously underreported.

      • Mie says

        Could you be more specific in the first part, please? The actual NNT for statins in primary prevention setting?

        As for the second part, I’ve read and commented many of your blog posts and I do agree with you on the issue of low risk patients. However, I cannot recall (nor couldn’t find one) a post that would’ve focused on the possible underreporting of the side effects of statins. Perhaps you’d care to elaborate? Or maybe even blog about it in the near future?

  7. says

    60% of subjects in PREDIMED were NOT on statins and the 3 arms had equivalent numbers on/off statins.

    If I had to choose between stroke or MI I would choose not to have a stroke.
    Barbara Roberts, MD

  8. battaggia says

    Dear Collegue,

    Savarese et al. (1) suggested a favorable effect of statins on major cardiovascular (CV) events in older people in the primary prevention setting. .Nevertheless the meta-analysis (1) suffers from various methodological pitfalls. For istance Savarese et al. did not try to carefully find unpublished raw data: the authors excluded the PROSPER (2) primary prevention data from their analysis of all causes mortality, although this information has been also available in the published work by Ray et al. since 2010 (3). The authors declared absence of publications bias, but publication bias is instead demonstrable fot the outcomes ‘myocardial infarction’ (Egger test p =0.013) and for the outcome ‘stroke’ (Effer test p=0.077). Savarese et al. interpreted the absence of efficacy of statins in prolonging survival to shortness of follow-up. However, previous studies performed in individuals with high CV baseline risk with a same median basal mortality rate demonstrated a survival beneficial effect of statin therapy after 1 year, as shown in the HPS trial (4). We believe that in older people without CV disease, statin therapy should be considered with caution, also considering the high prevalence of side-effects of these drugs in the real world, and the well-known inverse relationship between mortality and LDL cholesterol in the elderly (5).
    A complete critical appraisal of Savarese & coll. work is available (I’m worry.. only in italian Language) at http://www.ulss20.verona.it/data/29/Informazioni/InfoFarma_6.pdf

    Alessandro Battaggia MD a.battaggia@libero.it

    1. Savarese G, Gotto AM Jr, Paolillo S, et al. Benefits of statins in elderly subjects without established cardiovascular disease. a meta-analysis. Am Coll Cardiol. 2013 Aug 14. doi:pii: S0735-1097(13)03880-1. 10.1016/j.jacc.2013.07.069. [Epub ahead of print]

    2. Shepherd J, Blauw GJ, Murphy MB. Et al.; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–30.

    3. Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mortality in high-risk primary prevention – a meta-analysis of 11 randomized controlled trials involving 65 229 participants. Arch Intern Med 2010;170:1024-31.

    4. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.

    5. Petersen LK, Christensen K, Kragstrup J. Lipid-lowering treatment to the end? A review of observational studies and RCTs on cholesterol and mortality in 80+-year olds. Age and Ageing 2010;39:674–80.

    • Doc's Opinion says

      Doctor Battaggia. Thanks for sharing your thoughts on the meta-analysis by Savarese et al. It is extremely important to highlight the shortcomings of this type of research. Meta-analyses of this kind are often highly valuated by authors of clinical guidelines and therefore can be very influential when it comes to guiding therapy. Therefore I highly appreciate your analytical input.

  9. Richard says

    Great catch Doc! Thank you for pointing this out publicly and to the publishing journal. I hope the correction gets as much press and attention as the original article (though I doubt it will). I also hope the authors and reviewers are appropriately humbled by their mistake.

Let me know what you think!