I'll copy and paste in case it's behind a paywall:
October 25, 2023
Putting Coronary Artery Calcium on Computed Tomography into Context
Kirsten E. Fleischmann, MD, MPH, FACC, reviewing Tattersall MC et al. JAMA Intern Med 2023 Sep 25 Garg PK and Brown DL. JAMA Intern Med 2023 Sep 25
Among people without cardiovascular disease, CT-detectable CAC increased markedly with age in every demographic group.
Coronary artery calcium (CAC), noted as an incidental finding on chest computed tomography (CT) performed for other reasons, is increasingly reported, but should it engender more medication use, cardiology referrals, and stress testing as has been reported? Investigators sought to place incidentally noted coronary calcification in context by determining CAC prevalence by age, sex, race, and ethnicity among individuals who were enrolled in the MESA study. MESA involved about 6800 people (age range, 45–84; mean age, 62) who were free from clinical atherosclerotic cardiovascular disease (ASCVD) at enrollment approximately 20 years ago (Circulation 2006; 113:30. opens in new tab).
The prevalence of detectable CAC increased markedly with age in every demographic group. Men had a higher prevalence than women in each age-range category. Non-Hispanic white men, in whom CAC prevalence exceeded 50% by age 50 to 54, tended to have the highest prevalence.
COMMENT
Although the MESA study is not fully representative of the U.S. population, these data suggest that CAC on CT is common, particularly in non-Hispanic white men, and its prevalence rises substantially with age. In part because of the high prevalence with increasing age, the authors suggest that seeing CAC incidentally on chest CT done for other reasons should not lead reflexively to aspirin or statin treatment or to specialist referral. Rather, they advocate for comprehensive ASCVD risk assessment and discussion of patient preferences, an approach with which I agree. Editorialists note that randomized, controlled trials showing improved outcomes with CAC-based strategies are lacking, but they cite two ongoing trials that should give us more answers (ROBINSCA [Eur Heart J Cardiovasc Imaging 2020; 21:1216. opens in new tab] and CorCal. opens in new tab).
CITATIONS
Tattersall MC et al. Incidental coronary artery calcium on chest CT in persons without known atherosclerotic cardiovascular disease. JAMA Intern Med 2023 Sep 25; [e-pub]. (https://doi.org/10.1001/jamainternmed.2023.3317. opens in new tab)
I agree CAC is helpful. It convinced my husband to start a statin at age 66. He has high LDL but A1C below 5, normal blood pressure, and a healthy lifestyle with lots of exercise. I read a few studies indicating the lowest all-cause mortality is at LDL of 140. Your thoughts? Will taking a Vitamin K supplement mitigate the potential risks of statins Micki Jacobs discussed below, which I've also seen elsewhere?
Missing here are mechanisms of calcium deposition as CAC. One is inactivated matrix gla protein, a vitamin k-dependent protein that happens to need sufficient T3 (the so-called 'active' thyroid hormone made mostly in peripheral tissues from T4) to be created. MGP creation depends on enough T3 and endocrinology currently believes (operative word here is believes) that serum levels represent all tissue levels, but evidence is that there are disparities and insufficiency of enough T3 in some tissues in spite of TSH being so-called in-range or T3 or T4 serum levels 'normal.' Those on T4 monotherapy for hypothyroidism have aberrant serum proportions of T4/T3 and are known to be at higher risk of events.
In fact, vitamin K in all its forms, is a huge player in calcium regulation.
As you cite diabetes, obesity, and other diseases as increasing risk of events, look into how calcium dysregulation is also involved in their etiology.
Microcalcifications precede CAC - they are the beginning. Current technology can now see them; CAC seen via CT is further into the process of CAC deposition and this CT measurable CAC also represents calcium dysregulation that is an etiological factor in diabetes/cancer/etc.
Statins directly inhibit vitamin K2 actions, thus increasing CAC and their benefits are vastly overstated while their harms - messing with K actions being one - are missed.
See:
Historical review of the use of relative risk statistics the portrayal of the purported hazards of high LDL cholesterol and the benefits of lipid-lowering therapy (2023)
It's not lipids, it's calcium dysregulation that is behind the common chronic diseases.
And we've really messed up dietary lipids in response to misunderstandings and, since VK 'lives' in fats, we've inadvertently messed up VK. High VK1 oils, when hydrogenated, create aberrant dihydroxyphylloquinine, which has been incorrectly blamed for damages when it's really the messed up VK that is damaging so much.
See:
Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in beta cells (2023)
The assumption that statins stabilize calcium in plaques is just that... assumption. Justification. Attempts to reconcile beliefs in lipids and all the jillions of tests upon which we've based all our hopes. It's BS.
Extreme athletes tend to high CAC, also.
Those blue zone folks eat lots of VK in all forms - especially K2 - and they manage to avoid things that interfere with VK actions. We, however, have immersed ourselves in toxins that mess with calcium regulation and these include some drugs (warfarin, statins, bisphosphonates, etc), some food additives and maybe even water fluoridation. Forever chemicals, many Rx drugs, and other ubiquitous substances are based in F and F messes with Ca.
As to reduction of CAC... that's been an elusive goal.
But it just might be possible when all these factors are considered together, not as individual approaches, but as all influences on calcium regulation from signaling molecules to hardened CAC.
Interesting. Matt Budoff wrote a piece in 2020 that
evaluated "the population level prevalence of zero CAC and examine the 20-year trends of zero CAC and burden of cardiovascular risk factors, in the Beach Cities of Southern California/Los Angeles (LA) county vs other regions of California, from 2000 to 2020. The Beach Cities of LA have been recently classified as a “certified Blue Zone community” through implementation of community-based public health initiatives focused on well-being and cardiovascular disease (CVD) prevention. These policies are reflective of the combination of lifestyle patterns and environmental changes, that are observed in rare longevity hotspots/blue zones around the world, mainly coastal areas such as the island of Okinawa in Japan, the peninsula of Nicoya in Costa Rica, the island of Ikaria in Greece, and the Mediterranean island of Sardinia [15]. The phenomenon of blue zones, where people live longer, healthier and happier lives have been identified in specific geographical regions worldwide and are characterized by the highest concentrations of healthy centenarians [16]."
Lots of limitations to this study but they did find a higher prevalence of Zero CAC in the beach counties of LA. (which they deemed a blue zone)
There was less smoking, diabetes, and obesity in the LA beach counties.
I'm hoping my San Diego beach community of Encinitas is also a blue zone! Seems like there are less fat people here and I almost never encounter a smoker. In addition , tons of people are constantly out walking, biking, surfing, running and playing pickle ball.
Of course, it is entirely possible that the healthier people migrate to the beach towns and not that the beach town environment makes them healthier.
I've been putting together an article which defends the use of CAC against the major criticisms I see online. Here is what I had written regarding the radiation:
"The radiation exposure from CAC scans has decreased substantially in the last decade and is now very low, averaging 1 mSV. This is less radiation than the 1.2 mSv my St. Louis patients receive annually from natural exposure.
Risks of radiation doses below 100 mSv have been described by US and international radiation protection organization as meaningless because long-term effects are either too small to be observed or non-existent.
For comparison purposes, a typical mammogram uses 0.4 mSV, a chest X-ray uses 0.1 mSV. Two cardiac tests that are widely and often inappropriately utilized in the US , coronary angiography ( 5-10 mSv) and myocardial perfusion imaging stress tests (12-14 mSV) expose patients to 10 times the radiation that CAC scans do.
In addition, with CAC scans there is no risk associated with accessing the venous or arterial system and no risk of contrast reactions. There is little to no value in repeating a non-zero CAC scan so the maximum lifetime exposure for most will be 1 mSV."
I hope that you were not Googling while driving or riding a bike to work!
My major concern with CAC usage is inappropriate downstream testing.
But I believe "the risks of CAC are minimal when the test is ordered and acted upon by an enlightened physician." Such a physician could be a progressive preventive noninvasive cardiologist or a brilliant family doctor like yourself.
This is all so helpful, as the absolute amounts of radiation exposure really do inform my counseling with patients and their decisions. Thanks for compiling this CAC resource! I wish I could ride a bike to work, but probably safer as I’ve been hit by 2 cabs when biking in the city previously. And thanks for reading my Stack too! Big fan of yours as well.
And ps, consider replying directly under reader comments as substack then sends a notification, fortunately this reply showed up somehow in my app feed or I would have missed it 😊
Dr. Pearson, is there any information about the Calcium Scores of people who live in the, “Blue Zones?” Perhaps Loma Linda, Ca Blue Zone might have information. Regards, Mary Kay Grant
This is really a fantastic review, and I find it practice-changing.
I do have lingering concerns, however, that there aren’t enough outcomes data convincing us that CAC is really worth doing in terms of cost, radiation, exposure, actual ASCVD events rescues, etc, but I think we can assume benefits outweighs risks.
As I go into work this morning I did a really a quick Google search, and I did find the following study very reassuring in terms of radiation exposure though. It also validates the 1 mSv radiation dose exposure you quote and that most people will receive across different scanners, body sizes, etc:
“ Based upon current estimates, a single CAC scan at 1 mSv would increase the lifetime risk of fatal malignancy by 0.005 % for a number needed to harm of 1 out of 20,000 patients [6]. This is a persistent limitation in discussing the long term risks of medical imaging, though this should not diminish the responsibility of physicians in the field of cardiac imaging from operating under the principle of “as low as reasonably achievable.” Given the potential harm of 1/20,000, the understanding of number needed to benefit also is important. Based on the American College of Cardiology/American Heart Association guidelines [4, 5], those persons with scores >300 and those >75th percentile by age and gender would be up-classified in risk, requiring high intensity statin treatment. Thus, the number of patients identified as high risk (about 1/3 of those screened), would far outweigh the cancer risk of screening in this population. Thus, the potential benefit outweighs the potential risk in the case of screening for heart disease.”
I’m sure my cardiologist would agree with you - he introduced CAC testing into Australia many years ago against professional opposition that still persists.
He says every man over 55 and every women over 60 should have a CAC.
At 67 I was the poster child of asymptomatic health and lifestyle until he found my CAC score was over 8000. At 71 I had a quintuple bypass.
I have zero family history of heart problems but somehow inherited high Lp(a). I understand 1 in 5 may have elevated Lp(a).
Given your health system does not subsidise CAC testing, would Lp(a) testing be a useful pre-screening for CAC screening?
I don't think it is u unreasonable to add lipo (a) to the first lipid panel an individual gets. It is cheap, very accurate and confers considerable risk. I feel it is mandatory if the individual has a family hx of premature ASCVD.
Many have made the argument to do CAC on all. I am ok with that as long as the results are being reviewed by a physician who is "enlightened" and doesn't perform knee jerk unnecessary testing. If we are doing them, however, I would recommend earlier than age 55 in men, 60 in women.
Very unusual for the score to go down although I've seen folks on social media claim theirs have gone down. Nothing noninvasive removes calcium or calcified plaque from the arterial wall.
Second question more complicated. I'll plan on answering the more complicated questions in a follow up post.
The response from GP could have been more helpful. Depending on your age that score could indicate very high risk compared to average for your age, very low or average risk.
Other than usual variations between tests, does the CAC score ever go down? As noted, it may go up even though the composition of plaque may be "better". Also, should the CAC always be reviewed by a cardiologist? I paid for a test and the result (243) was sent to my GP, who commented "As expected - keep taking the statins"...
My interpretation of this Dr. Agatston's presentation to the Cleerly community is that stopping NEW plaques is essential with drugs and diet. However the body continues to calcify (stabilize) old plaques so the score continues to increase but slowly.
This study cited in "Eat Rich, Live Long" by Cummins documents that for all CAC score groups an annual increase of 15% or less restores the yearly risk of a major adverse event to background level, ~3%.
https://bmjopen.bmj.com/content/14/3/e077949
Is LDL cholesterol associated with long-term mortality among primary prevention adults? A retrospective cohort study From a large healthcare system
Hey I thought of you with this summary from NEJM Journal Watch. Interesting...
https://www.jwatch.org/na56613/2023/10/25/putting-coronary-artery-calcium-computed-tomography
I'll copy and paste in case it's behind a paywall:
October 25, 2023
Putting Coronary Artery Calcium on Computed Tomography into Context
Kirsten E. Fleischmann, MD, MPH, FACC, reviewing Tattersall MC et al. JAMA Intern Med 2023 Sep 25 Garg PK and Brown DL. JAMA Intern Med 2023 Sep 25
Among people without cardiovascular disease, CT-detectable CAC increased markedly with age in every demographic group.
Coronary artery calcium (CAC), noted as an incidental finding on chest computed tomography (CT) performed for other reasons, is increasingly reported, but should it engender more medication use, cardiology referrals, and stress testing as has been reported? Investigators sought to place incidentally noted coronary calcification in context by determining CAC prevalence by age, sex, race, and ethnicity among individuals who were enrolled in the MESA study. MESA involved about 6800 people (age range, 45–84; mean age, 62) who were free from clinical atherosclerotic cardiovascular disease (ASCVD) at enrollment approximately 20 years ago (Circulation 2006; 113:30. opens in new tab).
The prevalence of detectable CAC increased markedly with age in every demographic group. Men had a higher prevalence than women in each age-range category. Non-Hispanic white men, in whom CAC prevalence exceeded 50% by age 50 to 54, tended to have the highest prevalence.
COMMENT
Although the MESA study is not fully representative of the U.S. population, these data suggest that CAC on CT is common, particularly in non-Hispanic white men, and its prevalence rises substantially with age. In part because of the high prevalence with increasing age, the authors suggest that seeing CAC incidentally on chest CT done for other reasons should not lead reflexively to aspirin or statin treatment or to specialist referral. Rather, they advocate for comprehensive ASCVD risk assessment and discussion of patient preferences, an approach with which I agree. Editorialists note that randomized, controlled trials showing improved outcomes with CAC-based strategies are lacking, but they cite two ongoing trials that should give us more answers (ROBINSCA [Eur Heart J Cardiovasc Imaging 2020; 21:1216. opens in new tab] and CorCal. opens in new tab).
CITATIONS
Tattersall MC et al. Incidental coronary artery calcium on chest CT in persons without known atherosclerotic cardiovascular disease. JAMA Intern Med 2023 Sep 25; [e-pub]. (https://doi.org/10.1001/jamainternmed.2023.3317. opens in new tab)
Garg PK and Brown DL. Coronary artery calcium screening — Data first. JAMA Intern Med 2023 Sep 25; [e-pub]. (https://doi.org/10.1001/jamainternmed.2023.3250. opens in new tab)
I agree CAC is helpful. It convinced my husband to start a statin at age 66. He has high LDL but A1C below 5, normal blood pressure, and a healthy lifestyle with lots of exercise. I read a few studies indicating the lowest all-cause mortality is at LDL of 140. Your thoughts? Will taking a Vitamin K supplement mitigate the potential risks of statins Micki Jacobs discussed below, which I've also seen elsewhere?
Hi again Dr P, would you like to comment on this post?
Bob
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2809982?guestAccessKey=40f428d3-d7af-4358-9934-b80359118281&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamainternalmedicine&utm_content=olf&utm_term=092523&adv=000004677365
Missing here are mechanisms of calcium deposition as CAC. One is inactivated matrix gla protein, a vitamin k-dependent protein that happens to need sufficient T3 (the so-called 'active' thyroid hormone made mostly in peripheral tissues from T4) to be created. MGP creation depends on enough T3 and endocrinology currently believes (operative word here is believes) that serum levels represent all tissue levels, but evidence is that there are disparities and insufficiency of enough T3 in some tissues in spite of TSH being so-called in-range or T3 or T4 serum levels 'normal.' Those on T4 monotherapy for hypothyroidism have aberrant serum proportions of T4/T3 and are known to be at higher risk of events.
In fact, vitamin K in all its forms, is a huge player in calcium regulation.
As you cite diabetes, obesity, and other diseases as increasing risk of events, look into how calcium dysregulation is also involved in their etiology.
Microcalcifications precede CAC - they are the beginning. Current technology can now see them; CAC seen via CT is further into the process of CAC deposition and this CT measurable CAC also represents calcium dysregulation that is an etiological factor in diabetes/cancer/etc.
Statins directly inhibit vitamin K2 actions, thus increasing CAC and their benefits are vastly overstated while their harms - messing with K actions being one - are missed.
See:
Historical review of the use of relative risk statistics the portrayal of the purported hazards of high LDL cholesterol and the benefits of lipid-lowering therapy (2023)
It's not lipids, it's calcium dysregulation that is behind the common chronic diseases.
And we've really messed up dietary lipids in response to misunderstandings and, since VK 'lives' in fats, we've inadvertently messed up VK. High VK1 oils, when hydrogenated, create aberrant dihydroxyphylloquinine, which has been incorrectly blamed for damages when it's really the messed up VK that is damaging so much.
See:
Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in beta cells (2023)
The assumption that statins stabilize calcium in plaques is just that... assumption. Justification. Attempts to reconcile beliefs in lipids and all the jillions of tests upon which we've based all our hopes. It's BS.
Extreme athletes tend to high CAC, also.
Those blue zone folks eat lots of VK in all forms - especially K2 - and they manage to avoid things that interfere with VK actions. We, however, have immersed ourselves in toxins that mess with calcium regulation and these include some drugs (warfarin, statins, bisphosphonates, etc), some food additives and maybe even water fluoridation. Forever chemicals, many Rx drugs, and other ubiquitous substances are based in F and F messes with Ca.
As to reduction of CAC... that's been an elusive goal.
But it just might be possible when all these factors are considered together, not as individual approaches, but as all influences on calcium regulation from signaling molecules to hardened CAC.
Interesting. Matt Budoff wrote a piece in 2020 that
evaluated "the population level prevalence of zero CAC and examine the 20-year trends of zero CAC and burden of cardiovascular risk factors, in the Beach Cities of Southern California/Los Angeles (LA) county vs other regions of California, from 2000 to 2020. The Beach Cities of LA have been recently classified as a “certified Blue Zone community” through implementation of community-based public health initiatives focused on well-being and cardiovascular disease (CVD) prevention. These policies are reflective of the combination of lifestyle patterns and environmental changes, that are observed in rare longevity hotspots/blue zones around the world, mainly coastal areas such as the island of Okinawa in Japan, the peninsula of Nicoya in Costa Rica, the island of Ikaria in Greece, and the Mediterranean island of Sardinia [15]. The phenomenon of blue zones, where people live longer, healthier and happier lives have been identified in specific geographical regions worldwide and are characterized by the highest concentrations of healthy centenarians [16]."
https://www.sciencedirect.com/science/article/pii/S2666667720300982
Lots of limitations to this study but they did find a higher prevalence of Zero CAC in the beach counties of LA. (which they deemed a blue zone)
There was less smoking, diabetes, and obesity in the LA beach counties.
I'm hoping my San Diego beach community of Encinitas is also a blue zone! Seems like there are less fat people here and I almost never encounter a smoker. In addition , tons of people are constantly out walking, biking, surfing, running and playing pickle ball.
Of course, it is entirely possible that the healthier people migrate to the beach towns and not that the beach town environment makes them healthier.
Thus, this is MOOP
Dr. P
Ryan,
Thanks for your thoughtful comment.
I've been putting together an article which defends the use of CAC against the major criticisms I see online. Here is what I had written regarding the radiation:
"The radiation exposure from CAC scans has decreased substantially in the last decade and is now very low, averaging 1 mSV. This is less radiation than the 1.2 mSv my St. Louis patients receive annually from natural exposure.
Risks of radiation doses below 100 mSv have been described by US and international radiation protection organization as meaningless because long-term effects are either too small to be observed or non-existent.
For comparison purposes, a typical mammogram uses 0.4 mSV, a chest X-ray uses 0.1 mSV. Two cardiac tests that are widely and often inappropriately utilized in the US , coronary angiography ( 5-10 mSv) and myocardial perfusion imaging stress tests (12-14 mSV) expose patients to 10 times the radiation that CAC scans do.
In addition, with CAC scans there is no risk associated with accessing the venous or arterial system and no risk of contrast reactions. There is little to no value in repeating a non-zero CAC scan so the maximum lifetime exposure for most will be 1 mSV."
I hope that you were not Googling while driving or riding a bike to work!
My major concern with CAC usage is inappropriate downstream testing.
But I believe "the risks of CAC are minimal when the test is ordered and acted upon by an enlightened physician." Such a physician could be a progressive preventive noninvasive cardiologist or a brilliant family doctor like yourself.
p.s. I'm a big fan of your Substack!
This is all so helpful, as the absolute amounts of radiation exposure really do inform my counseling with patients and their decisions. Thanks for compiling this CAC resource! I wish I could ride a bike to work, but probably safer as I’ve been hit by 2 cabs when biking in the city previously. And thanks for reading my Stack too! Big fan of yours as well.
And ps, consider replying directly under reader comments as substack then sends a notification, fortunately this reply showed up somehow in my app feed or I would have missed it 😊
Thank you. I thought I was replying directly under the reader comments as I think I am doing now.
This one came through 👍
Dr. Pearson, is there any information about the Calcium Scores of people who live in the, “Blue Zones?” Perhaps Loma Linda, Ca Blue Zone might have information. Regards, Mary Kay Grant
This is really a fantastic review, and I find it practice-changing.
I do have lingering concerns, however, that there aren’t enough outcomes data convincing us that CAC is really worth doing in terms of cost, radiation, exposure, actual ASCVD events rescues, etc, but I think we can assume benefits outweighs risks.
As I go into work this morning I did a really a quick Google search, and I did find the following study very reassuring in terms of radiation exposure though. It also validates the 1 mSv radiation dose exposure you quote and that most people will receive across different scanners, body sizes, etc:
“ Based upon current estimates, a single CAC scan at 1 mSv would increase the lifetime risk of fatal malignancy by 0.005 % for a number needed to harm of 1 out of 20,000 patients [6]. This is a persistent limitation in discussing the long term risks of medical imaging, though this should not diminish the responsibility of physicians in the field of cardiac imaging from operating under the principle of “as low as reasonably achievable.” Given the potential harm of 1/20,000, the understanding of number needed to benefit also is important. Based on the American College of Cardiology/American Heart Association guidelines [4, 5], those persons with scores >300 and those >75th percentile by age and gender would be up-classified in risk, requiring high intensity statin treatment. Thus, the number of patients identified as high risk (about 1/3 of those screened), would far outweigh the cancer risk of screening in this population. Thus, the potential benefit outweighs the potential risk in the case of screening for heart disease.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752888/
Thank you.
Super post, thank you!
Thank you this post Dr Pearson.
I’m sure my cardiologist would agree with you - he introduced CAC testing into Australia many years ago against professional opposition that still persists.
He says every man over 55 and every women over 60 should have a CAC.
At 67 I was the poster child of asymptomatic health and lifestyle until he found my CAC score was over 8000. At 71 I had a quintuple bypass.
I have zero family history of heart problems but somehow inherited high Lp(a). I understand 1 in 5 may have elevated Lp(a).
Given your health system does not subsidise CAC testing, would Lp(a) testing be a useful pre-screening for CAC screening?
Bob,
I don't think it is u unreasonable to add lipo (a) to the first lipid panel an individual gets. It is cheap, very accurate and confers considerable risk. I feel it is mandatory if the individual has a family hx of premature ASCVD.
Many have made the argument to do CAC on all. I am ok with that as long as the results are being reviewed by a physician who is "enlightened" and doesn't perform knee jerk unnecessary testing. If we are doing them, however, I would recommend earlier than age 55 in men, 60 in women.
Dr. P
Very unusual for the score to go down although I've seen folks on social media claim theirs have gone down. Nothing noninvasive removes calcium or calcified plaque from the arterial wall.
Second question more complicated. I'll plan on answering the more complicated questions in a follow up post.
The response from GP could have been more helpful. Depending on your age that score could indicate very high risk compared to average for your age, very low or average risk.
Other than usual variations between tests, does the CAC score ever go down? As noted, it may go up even though the composition of plaque may be "better". Also, should the CAC always be reviewed by a cardiologist? I paid for a test and the result (243) was sent to my GP, who commented "As expected - keep taking the statins"...
Steve,
Ref:
https://cleerlyhealth.com/transforming-cardiac-care/session-6?_hsmi=271270062
My interpretation of this Dr. Agatston's presentation to the Cleerly community is that stopping NEW plaques is essential with drugs and diet. However the body continues to calcify (stabilize) old plaques so the score continues to increase but slowly.
Also ref:
https://pubmed.ncbi.nlm.nih.gov/15059806/
This study cited in "Eat Rich, Live Long" by Cummins documents that for all CAC score groups an annual increase of 15% or less restores the yearly risk of a major adverse event to background level, ~3%.