IBIS 4 – High-Dose Rosuvastatin Shrinks Coronary Plaque

Women and CVDOne year of treatment with the highest dose of the cholesterol-lowering drug Rosuvastatin can shrink plaque inside the arteries of patients who have had a certain type of heart attack known as ST-segment elevation myocardial infarction (STEMI), according to a new study presented at European Society of Cardiology Congress 2014.

BARCELONA, Spain – Tuesday 2 September 2014: One year of treatment with the highest dose of the cholesterol-lowering drug Rosuvastatin can shrink plaque inside the arteries of patients who have had a certain type of heart attack known as ST-segment elevation myocardial infarction (STEMI), according to a new study presented at ESC Congress 2014 (http://www.escardio.org/about/press/press-releases/esc14-barcelona/Pages/hotline-five-ibis-4.aspx).

Although STEMI patients often undergo a revascularization procedure (angioplasty or stent insertion) to unblock the “culprit” artery that caused their heart attack, they remain at increased risk for similar events due to plaque formation in other untreated coronary arteries.

The IBIS-4 study, which was published simultaneously in the European Heart Journal is the first to use ultrasound imaging inside coronary arteries both at the time of heart attack and after 13 months of treatment to show the benefit of high-dose statin therapy on plaque burden. The study was an investigator-initiated trial performed at five sites in Europe (University Hospitals of Bern, Copenhagen, Geneva and Zürich and Cardiocentro Lugano) without support from a pharmaceutical cholesterol-lowering manufacturer.

Previous work has shown that high-dose Rosuvastatin can reduce plaque size in patients with stable chronic atherosclerotic vascular (coronary) disease, but until now this has not been specifically investigated in arteries of patients with acute heart attacks, a setting known to harbour additional high risk plaques that can be the source for future cardiovascular events.

IVUS 3This is also the first study is the first to use intracoronary ultrasound to assess the actual plaque composition and the plaque phenotype, and to observe how both respond to high dose potent statin treatment.

IBIS-4 included 103 acute heart attack patients who were first successfully treated to unblock the culprit vessel. Subjects then underwent imaging, both at the start of the study and then after 13 months of high-intensity Rosuvastatin treatment (40 mg/d), to assess the drug’s impact on their non-culprit arteries. Rosuvastatin was given at a dose of 40 mg daily. After 13 months, ultrasonography showed that 85% of patients had regression of plaque in at least one artery, and 56% had regression in both. Overall, intracoronary plaque volume was reduced by a mean of -0.9% (p=0.007), with a mean change of the total atheroma volume of -13.7 mm3 (p=0.006). Although the reduction in plaque volume was independent from cholesterol levels at baseline, it was directly related to the extent of cholesterol reduction at 13 months. As expected, Rosuvastatin also had beneficial effects on lipoprotein levels. Low-density lipoprotein (LDL) decreased from a median of 3.29 mmol/L at baseline to 1.89 mmol/L (p<0.001), corresponding to a 43% reduction. A total of 44% of patients achieved a guideline-recommended LDL level of less than 1.8mmol/L. The beneficial effects of high-dose statin therapy on coronary plaque regression previously observed in patients with stable coronary artery disease (ASTEROID study) can be extended to those at highest risk for cardiovascular complications, namely patients with acute heart attacks. This explains at least in part the clinical benefit of high-dose statin therapy in patients with heart attacks.


25 thoughts on “IBIS 4 – High-Dose Rosuvastatin Shrinks Coronary Plaque

  1. Very interesting article! This is my first comment here, and I have to say I’m really enjoying reading your articles, very informative.

    Do you have any thoughts on the different types of statins, would you recommend one over another, or I guess different statins may be suited to different people.

    Having read the article about “Elevated lipid years” I am now re-considering whether I should use statins.

    I had my first cholesterol test at 34 and had borderline high cholesterol, I then worked at sea for a few years and my cholesterol increased dramatically (278mg/dl Total, 216mg/dl LDL) I have no doubt that my life on board played a big part in this, the lack of sleep, lack of control over my diet, stress and alcohol, although I dont think it is the only factor as I had high cholesterol before.

    Since returning to land, I have made a number of changes to reduce my cholesterol levels including cardio and weight training sessions three times a week, eating fiber rich fruits and vegetables at every meal, swapping white bread for multigrain bread, drinking alcohol only once or twice a week. Vitamin D + K Daily, Oily fish 1 to 2 times a week. No eggs, swapping red meat for white meat or fish. I dont smoke

    My bodyweight and height is 1.83cm and 185lbs, 34 inch waist which has been the same since I was 25, At 20 I had a 32 inch waist.

    After discussing with my results with my doctor I said I did not want to take statins, as I believed that without learning to control my own cholesterol levels through diet and exercise, I would never get to the root of the problem and simply be masking bad diet.

    However with all these changes, my cholesterol is reducing very very slowly.

    It has taken me about three years just to get from 278 down to 243 for my total. And my LDL from 216 to 169.
    I had 4 cholesterol tests between 2011 and 2014 and there is a continous downward trend but its slow. Is it worth using statins short term to speed up the process of getting it down quicker. My assumption being that if my diet is reducing my cholesterol levels slowly it make take years just to get into the normal range. If my diet is facilitating a downward trend would it be wise to use statins to “get it down” and then come off and maintain normal levels through my diet? Perhaps my diet is simply not aggresive enough.

    I have also wondered if other factors are at play for this slow progress. I recently read a study that suggested Asthmatics compared to non-asthmatics, had significantly higher levels of inflammatory markers including C-reactive protein and fibrinogen. Patients with a history of asthma but not currently requiring daily medication had intermediate levels of these inflammatory markers

    I have Asthma, Eczema, peanut allergy, dairy, wheat, yeast and egg intolerance and various other airborn allergens (identified by both RAST test and ELISA test). My asthma and eczema and most allergies (with exception of peanut) are under control through diet and probably the passing of time too.

    Do you have any thoughts on whether these inflammatory conditions could play a part in elevated cholesterol levels and slow changes when implementing other diet and lifestyle factors?

    Anyway sorry for my rambling response! I am just putting my own experience out there, not looking for an answer or solution, just interested in any thoughts, I will be discussing this fully with my own GP.

    BTW I had a search of your site for anything about Statins and calcification of the arteries. What are your thoughts on this (worthy of an article perhaps?) Would Vitamin K be a useful tool in minimising the risk of this side effect, if it is indeed a side effect.

    Anyway thanks for putting these amazing articles out there,

    • Hi Morris

      Only 2 statins have been definitively shown to reduce plaque volume. The ASTEROID study demonstrated Atorvastatin at 80 mg/d and Rosuvastatin 40 mg/d both reduced plaque volume (identically) over time.

      To make an informed decision whether you should start a statin you need to undergo “risk stratification”. I have written extensively on this (late 2014 and early 2015) using clinical guidelines as well as a risk stratification programme (e.g. Framingham Risk Score) or the program the AHA published in Oct 2013. The presence of sub clinical atherosclerotic vascular disease either using Carotid Ultrasound or coronary calcium score (CCS) will upgrade the mandate for statin therapy.

      Chronic inflammation causes high levels of oxidised Apo B lipoproteins and increases the burden of atherosclerosis.

      I have previous written about Vit K2 and vascular calcification (Jan 18 2013).

      Regards Cardiologydoc

      • “Only 2 statins have been definitively shown to reduce plaque volume. The ASTEROID study demonstrated Atorvastatin at 80 mg/d and Rosuvastatin 40 mg/d both reduced plaque volume (identically) over time.”

        Well… The trials used to prove this claim were somewhat designed in a matter disfavouring the control drug, as the dose of the “weaker” statins in the control group wasn’t titrated to match LDL levels and/or percentage LDL reduction. From everything we know by now, I don’t think anyone without conflict of interest really would argue for some “magical” property of atorvastatin and rosuvastatin, as long as you don’t need them to reduce LDL below threshold for regression to occur.

        Starting with an LDL around 200 mg/dl every physician will try rosuvastatin or atorvastatin first, of course. But even with 40mg of Crestor as monotherapy I would NOT expect regression to occur, given that we can estimate to reach an LDL-C of maybe slightly below 100 mg/dl in most cases.

  2. Hi, would you be able to share your personal observations on the time frame for changes in LDL/HDL/TC with dietary shifts. e.g would people making a shift from a traditional western diet to a paleo diet see changes within weeks/months/several months.Thanks

    • Hi Neil

      Within 8 weeks of a low carbohydrate high fat (LCHF) lifestyle we see dramatic drop TG; elevation in HDL. LDL often drops or stays static but the LDL particle size increases (good prognosis) and the TC may elevate due to elevation in HDL/ LDL. The TG/ HDL ratio dramatically improves.


      • In what percentage of your patients???
        My own (untreated at the time) LDL went from ~130 to over 200 within a few months and from what I read in different online forums this seems to be pretty standard with the socalled “paleo” approach. I guess you are not the kind of cardiologist who will tell me this is OK because of particle size… I actually NEVER found a single account of someone with an acceptable lipid profile on that kind of diet.

  3. Hi Walter

    Thanks for the comment. Actually I’m a great fan and proponent of LCHF keto-adaptation and have prescribed keto-diets for 5 years (including Paleo). I have advanced experience with lipoprotein changes on ketogenic and LCHF diets and am very familiar with elevated LDL on Paleo diets representing “particle size.” You have to be sure however that the elevated LDL is due to particle size and not particle number. The best way of distinguishing is to do Apo B levels as this is an exact marker of particle number including other Apo B particle that are atherogenic (IDL and VLDL and Lipoprotein “a”).

    Hope this helps

    • I have been considering a low carb diet, yet not so keen on the idea of the high fat part.

      I read some different studies that suggested that Saturated fat inhibits the production of Nitric oxide. Another one refers to fatty acids affecting NO.

      Conclusions—Elevated levels of common FFA found in human serum activate IKK in endothelial cells leading to reduced NO production, and thus may serve to link pathways involved in inflammation and endothelial dysfunction

      I was wondering if the high fat consumption associated with some types of ketogenic diet and Paleo diet would not reduce NO, which as I understand is beneficial in maintaining endothelial function.

      I understand ketogenic diets significantly burns more calories, but if fat consumption is higher than “normal” couldnt this impair optimum levels of NO.
      Or is it a case that when the body is in a ketogenic state, that other processes are taking place which offset the effects of higher fat intake (ie is it being used for fuel and not getting into the bloodstream where it can supress NO)

      Either way it makes me wonder if a low carb, low fat, moderate protein diet might be a safer option.

      What do you think about Intermittent Fasting, another diet concept that seems popular at the moment and claims various health benefits in addition to weight loss.

      • Intermittent fasting has benefit particularly if on a ketogenic diet. I don’t think we have enough data on NO inhibition from LCHF ketogenic diets but the proof of concept of LCHF in metabolic syndrome and Type 2 diabetes is impressive.

  4. Thanks for replying. As an aside do you read anything of note in the INCREASED calcification seen following intensive statin therapy? As a non clinician my preference is for calcified stable plaques vs thin fibrous caps with concomitant increased risk of rupture, and resultant heightened morbidity/mortality i.e I like the morphological change in plaques post statin.

    • Isn’t this somewhat in conflict with Vitamin K2 supplementation that you wrote about a few years ago? Would you argue that the inhibiting effect of K2 on calcification could reduce the plaque stabilizing effect of statins? Very confusing…

  5. Hi Walter

    Thanks for your comment. I don’t think we know enough about the biology of plaque stabilization. What we do know is the high dose potent statins reduce plaque volume. We also know that people who take long term statin therapy do not necessarily stop increasing coronary calcium scores yet their prognosis improves suggesting that calcification of plaque is part of possibly stabilizing the plaque. The data on K2 and vascular calcification is in its infancy with no trials or studies on long term benefit or risk to plaque long term. I’m speculating but perhaps in the presence of K2 and statins the plaques MAY heal with no calcification???


  6. Wonderful Resource. Question on VEGANISM. Two years ago, at age 64, after a lifetime of “borderline” lipid values and a CT-calcium score of 153, I switched to a totally whole food plant-based. LDL plummeted to 70, total 128, HDL 42. on 5 mg lipitor – great numbers but…. Sadly two years later my CT score jumped to 221. Clearly LDL is not the only culprit. I see that I need to increase my statin level for plaque stability.

    Should vegans, in addition to B12 be taking 300µg of K2? Plants don’t contain K2 and I am concerned that vegans may be more susceptible to calcium plaques.

    • Greetings

      Thanks for taking the time to put your worries to print. Your LDL value as a vegan is great BUT your HDL (42) and Non-HDL (86) are sub optimal indicating your atherogenic load (non-HDL or Apo B) is not optimal. K2 does seem to prevent vascular calcification but we have NO definitive studies and you are correct there is no reliable source of K2 in the vegetable kingdom. So you are stuck with two options….increasing your statin therapy and adding K2 as you indicated as a supplement.


      • Isn’t it that the calcifications seen in these CTs occur in plaques that are actually old and there for years if not decades? I think some cardiologists somewhat overinterpret these results if taken in series of measurements? The course of calcification is the course of plaque growth in the past it seems. Even more important, there seems to be no doubt that statins reduce risk BUT are associated with increased calcification at least in certain subgroups of patients. That leaves me thinking that repeted(!) cardio-CTs aren’t jsutified and just an unnecessary exposition to ionizing radiation…

  7. Thanks for the responses. I do know my particle size and count is borderline despite the low LDL. I suppose that’s just the nature of how my liver handles cholesterol:-( My total/HDL=3 which is better than the 3.5 optimum – isn’t that the important number despite the absolute value of HDL being somewhat low?
    Walter – I was led to believe that calcium plaque progression >15%/year was a concern. Wouldn’t a two-year follow-up CT score be justified to determine if measures one is taking through diet and medication are adequate?

    I wonder if once a plaque is formed, does it self-generate more crystallization with only a weak dependence on LDL concentration.

    • As far as I(!) know there is no reliable data on the progression of calcium scores in treated populations. Pretty large increases under statin treatment seem to be standard and YET be associated with higly significant risk reduction. Some people call the calcium in this context even “nature’s stent”, although this may be somewhat hyperbole. I know many cardiologists interpret increased calcium under statin as lesion healing.
      Calcification is a VERY late stage in plaque development Plaques grow for decades and in most peolpe only start to calcify after the age of 50. The fact that there IS calcification is just a surrogate for a whole lot of plaque. But after a certain time of lipid lowering therapy the fatty cores of the plaques, which are the real problem and cause events, are essentialls sucked out of the plaques for the most part (Think of the ever spreading Kaplan-Meier curves!) and I really don’t think calcification is overly important in this context.

  8. Have recently come across your blog. Thank you. I have been taking 5 mg/d Crestor for about 8-10 y and have “stiff” and weakened muscles, lower energy, cramping, “foggy head”, decreased libido, focus and memory. I eat nutritiously and and lost 12 lbs in the past 6 months (am now 160 lbs and 5′ 7″). I am 73 y and have 9 stents; the last is a drug eluting stent and hence I am also on Plavix. My Current total cholesterol (122), HDL (48), LDL (56), Triglycerides (88). Due to the side effects I have experiences that may be statin-related I would like to go off Crestor. My cardiologists advise I stay on the drug given my history and other potential beneficial effects of Crestor (plaque-stabilization). I also have chronic low platelets (16-20K) and also take a beta and Ca-2 channel blocker and Co-Q. Although I am a trained Ph.D. biologist, I find the current literature confusing. Any suggestions regarding ceasing Crestor and/or alternative approaches to managing my CAD will be appreciated.

  9. Thank you very much for your response. My current (56) and past 10y LDL levels (range: 80-46) are quite acceptable. Is that likely due to the 5 mg/d Crestor I take? diet? exercise? What I’m trying to get at is if I ditch the Crestor and keep up my diet and exercise, how much would my lipid levels change? If not too much, then even trying a PCSK9-inhibitor may be overkill. Would it be worthwhile to go off Crestor for a month and evaluate lipid levels them? Also, the effect of 40 mg/d Crestor seems minute; less than 1% decrease in plaque volume, so is this really a good justification for continuing Crestor, especially since I only take 5 mg/d?

  10. Hi Stephen

    The statin effect on plaque regression and plaque stability is an important mechanism explaining better outcome with statin therapy. Whilst the plaque regression at 1% per year may sound small it is important to note that a small change in vessel radius will have a very large influence (4th power) on its resistance to flow (Poiseuille’s equation). This equation may be applied not only to a single vessel, but can also be used to describe flow through a network of vessels (i.e., the vascular bed of an organ or the even your entire systemic circulatory system). So the statin effect on small and medium sized vessel are critical to reducing events. It is evident from the IVUS trials that this plaque regression/ stability is achieved best with LDL < 70 and it is these levels of LDL easily achieved with PCSK9-I alone or in combination with statin therapy. We have NO trials to show plaque regression without statins. So if I had coronary/ vascular disease if would certainly take as much statin +/- PCSK9-I to achieved LDL < 70.

    Hope this helps

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