Questioned - Statin Recommendations / Risk Calculator / American College of Cardiology/American Heart Association (ACC/AHA) guidelines on assessment of cardiovascular risk1 and on treatment of blood cholesterol
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"statinization." It is uncertain whether this would be one of the greatest achievements or one of the worst disasters of medical history..... Based on the evidence of overprediction derived even in the original validation of the risk calculator and subsequent independent validations, perhaps about half of statin candidates may actually have a true 10-year risk of less than 7.5%..... when looking at the granularity of the predictors (eg, how lipids should be represented), high-density lipoprotein cholesterol was selected even though it is clearly noncausally related to coronary artery disease,7 an example of how highly significant predictors may have little to do with how treatment works..... even though many randomized trials on statins have been published, there is no randomized evidence that this particular risk model, rather than any of its predecessors built with the same, similar, or other predictors, would identify the patients who benefit most from statin therapy and that the optimal treatment threshold is 5%, 7.5%, or even 2.5% or 15%. Information on potential statin harms (myopathy, diabetes, and more) is accumulating and concerning but also less systematically collected and thus carries more uncertainty than the benefits. The exact incidence of harms could markedly affect the optimal risk threshold for treatment..... experts who made the influential treatment
recommendations......critics point out that 8 of the 15 panelists had industry ties..... Perhaps these panels should include knowledgeable patients who are well versed in understanding the scientific background (eg, predictive models), many methodologists (ideally working in different applied fields), and excellent clinicians/scientists from other specialties whose practice volume is not at stake. Content experts could serve as nonvoting members or advisors to such panels.
American College of Cardiology/American Heart Association (ACC/AHA) guidelines on assessment of cardiovascular risk1 and on treatment of blood cholesterol, which included recommendations for primary prevention with statins,2 came under intense criticism immediately with their release. Main concerns focused on flawed methods (problems with the risk calculation),3 ethics (conflicts of interest),4 and inferences (too many people offered treatment)........reliance on the new risk prediction algorithm could put many primary prevention patients on statin therapy where there is little trial evidence, ......It is reasonable to ask if any global risk prediction score is needed in 2013 to allocate statin therapy in primary prevention. .... As shown in figure 1, in all three of these primary prevention cohorts, the new ACC/AHA risk prediction algorithm systematically overestimated observed risks by 75-150%, roughly doubling the actual observed risk. ......new criteria could result in more than 45 million middle-aged Americans who do not have cardiovascular disease being recommended for consideration of statin therapy (33 090 000 at ≥7⋅5% 10-year risk; 12 766 000 at >5⋅0-7⋅4% 10-year risk); this is about one in every three American adults, many of whom are already on statin treatment under the older US guidelines...... cardiologists now understand that statins cannot be recommended simply on the basis of high risk without regard for underlying clinical conditions. As examples, the CORONA10 and AURORA11trials enrolled individuals with very high vascular risk in the settings of heart failure or renal failure and found no evidence of event reduction with statin therapy despite large reductions in LDL cholesterol."
Statins: new American guidelines for prevention of cardiovascular disease - Comment
Paul M Ridker Nancy R Cook
Lancet 0 November 2013
Guidelines released on Nov 13, 2013, by the American Heart Association (AHA) and the American College of Cardiology (ACC) for the management of cholesterol are a major step in the right direction.1 These new guidelines emphasise prevention of stroke as well as heart disease, focus appropriately on statin therapy rather than alternative unproven therapeutic agents, and recognise that more intensive treatment is superior to less intensive treatment for many patients. Furthermore, the new ACC/AHA guidelines show that for individuals in whom statin therapy is clearly indicated (such as those with previous vascular disease or LDL cholesterol ≥4⋅9 mmol/L [190 mg/dL]) the benefits on heart attack, stroke, and cardiovascular death significantly outweigh the risks for developing diabetes or myopathy. Moreover, by eliminating emphasis on LDL treatment targets and the need to measure concentrations of creatine kinase during follow-up, the new guidelines greatly simplify care for the general medicine community. These changes are substantial and will improve patient care.
It is in the realm of primary prevention that the new guidelines are likely to be more controversial. The ACC/AHA guidelines use a newly developed risk prediction algorithm based on "hard" atherosclerotic events2 to recommend initiation of statin therapy in primary prevention patients with a predicted 10-year risk of greater than or equal to 7⋅5%, and consideration of statin therapy in patients with 10-year risks of between 5% and 7⋅5%. In patients with type 1 or type 2 diabetes, the threshold of greater than or equal to 7⋅5% is used to select between high-intensity and moderate-intensity statin regimens, defined as daily regimens that reduce LDL cholesterol by more than 50% or between 30% and 50%. As described in the guidelines, these new criteria could result in more than 45 million middle-aged Americans who do not have cardiovascular disease being recommended for consideration of statin therapy (33 090 000 at ≥7⋅5% 10-year risk; 12 766 000 at >5⋅0-7⋅4% 10-year risk); this is about one in every three American adults, many of whom are already on statin treatment under the older US guidelines.
It is reasonable to ask if any global risk prediction score is needed in 2013 to allocate statin therapy in primary prevention. Between 1995 and 2008, six major primary prevention trials, which included more than 55 000 men and women, showed statins to be effective in primary prevention for the reduction of myocardial infarction and stroke among those with raised LDL cholesterol (WOSCOPS, MEGA),3, 4 reduced HDL cholesterol (AFCAPS/TexCAPS),5 raised concentrations of C-reactive protein (JUPITER),6 diabetes (CARDS),7 or hypertension (ASCOT-LLA).8 Thus, trial-based guidelines that rely on randomised experiments rather than estimates from epidemiological models could instead be used to write statin guidelines.9
No trial of statin therapy has ever used a global risk prediction score as an enrolment criterion, so basing prescription on such a metric might be difficult to defend in an evidence-based climate. In addition, trial data contradict statements that high absolute risk always predicts statin efficacy; cardiologists now understand that statins cannot be recommended simply on the basis of high risk without regard for underlying clinical conditions. As examples, the CORONA10 and AURORA11trials enrolled individuals with very high vascular risk in the settings of heart failure or renal failure and found no evidence of event reduction with statin therapy despite large reductions in LDL cholesterol.
Other than age, the major drivers of high global risk are smoking and hypertension, for which the interventions of choice should be to eliminate cigarette use and to lower blood pressure, rather than to write a prescription for statin therapy. This is well acknowledged in the new guidelines that also address lifestyle factors, but can be confusing if applied without physician discretion. Consider a 55-year-old male smoker with hypertension (untreated systolic blood pressure of 145 mm Hg) with LDL cholesterol of 1⋅9 mmol/L (75 mg/dL) and HDL cholesterol of 1⋅3 mmol/L (50 mg/dL). According to the new ACC/AHA algorithm, this patient has a 10-year risk of 9⋅6% and thus is recommended for a statin, despite his already very low LDL cholesterol. Alternatively, consider a 60-year-old non-smoking woman with normal blood pressure (120 mm Hg) and HDL cholesterol of 1⋅3 mmol/L (50 mg/dL), but substantially raised LDL cholesterol of 4⋅7 mmol/L (180 mg/dL). According to the new risk algorithm and guideline, her 10-year risk is 3⋅8% and she should not be considered for statin therapy at all. Thus, as with all guidelines, context will continue to have a role in physicians' decision making. More important than absolute risk for the patient is the projected treatment effect for the individual given his or her risk factors.
Another concern for clinicians is whether the new prediction algorithm created by the ACC/AHA correctly assesses the level of vascular risk. To be useful, prediction models must not only discriminate between individuals with and without disease, but must also calibrate well so that predicted risk estimates match as closely as possible the observed risk in external populations.12 We calculated predicted 10-year risks of the same atherosclerotic events using the new ACC/AHA risk prediction algorithm and compared these estimates with observed event rates in three large-scale primary prevention cohorts, the Women's Health Study,13 the Physicians' Health Study,14 and the Women's Health Initiative Observational Study.15
As shown in figure 1, in all three of these primary prevention cohorts, the new ACC/AHA risk prediction algorithm systematically overestimated observed risks by 75-150%, roughly doubling the actual observed risk. As shown in figure 2, similar overestimation of risk was observed in two external validation cohorts used by the guideline developers themselves, an issue readily acknowledged in the report.2 Thus, on the basis of data from these five external validation cohorts, it is possible that as many as 40-50% of the 33 million middle-aged Americans targeted by the new ACC/AHA guidelines for statin therapy do not actually have risk thresholds that exceed the 7⋅5% threshold suggested for treatment. Miscalibration to this extent should be reconciled and addressed in additional external validation cohorts before these new prediction models are widely implemented. It is possible, for example, that the five external validation cohorts are more contemporary than the cohorts used in the risk prediction algorithm and thus reflect secular improvements in overall health and lifestyle patterns in the USA over the past 25 years.
The recent ACC/AHA cholesterol guidelines take several major steps forward that will simplify and improve care for higher risk patients, including those with diabetes. At the same time, reliance on the new risk prediction algorithm could put many primary prevention patients on statin therapy where there is little trial evidence, while potentially denying statin therapy to other patients despite trial evidence of efficacy. In primary prevention, instead of predicting risk and presuming benefit, an alternative and simpler policy of asking "what works?" and "in whom?" based on trial evidence would reduce this problem and result in evidence-based public health recommendations for statin therapy in patient groups for whom we have hard data showing efficacy.
PMR receives investigator-initiated research support from Amgen, AstraZeneca, Novartis, and Pfizer and is listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Siemens and AstraZeneca. NRC declares that she has no conflicts of interest.
Risk Calculator for Cholesterol Appears Flawed
By GINA KOLATANOV. 17, 2013
Last week, the nation's leading heart organizations released a sweeping new set of guidelines for lowering cholesterol, along with an online calculator meant to help doctors assess risks and treatment options. But, in a major embarrassment to the health groups, the calculator appears to greatly overestimate risk, so much so that it could mistakenly suggest that millions more people are candidates for statin drugs.
The apparent problem prompted one leading cardiologist, a past president of the American College of Cardiology, to call on Sunday for a halt to the implementation of the new guidelines.
"It's stunning," said the cardiologist, Dr. Steven Nissen, chief of cardiovascular medicine at the Cleveland Clinic. "We need a pause to further evaluate this approach before it is implemented on a widespread basis."
The controversy set off turmoil at the annual meeting of the American Heart Association, which started this weekend in Dallas. After an emergency session on Saturday night, the two organizations that published the guidelines - the American Heart Association and the American College of Cardiology - said that while the calculator was not perfect, it was a major step forward, and that the guidelines already say patients and doctors should discuss treatment options rather than blindly follow a calculator.
Dr. Sidney Smith, the executive chairman of the guideline committee, said the associations would examine the flaws found in the calculator and determine if changes were needed. "We need to see if the concerns raised are substantive," he said in a telephone interview on Sunday. "Do there need to be changes?"
The problems were identified by two Harvard Medical School professors whose findings will be published Tuesday in a commentary in The Lancet, a major medical journal. The professors, Dr. Paul M. Ridker and Dr. Nancy Cook, had pointed out the problems a year earlier when the National Institutes of Health's National Heart, Lung, and Blood Institute, which originally was developing the guidelines, sent a draft to each professor independently to review. Both reported back that the calculator was not working among the populations it was tested on by the guideline makers.
That was unfortunate because the committee thought the researchers had been given the professors' responses, said Dr. Donald Lloyd-Jones, co-chairman of the guidelines task force and chairman of the department of preventive medicine at Northwestern University.
Drs. Ridker and Cook saw the final guidelines and risk calculator on Tuesday at 4 p.m., when a news embargo was lifted, and saw that the problems remained.
On Saturday night, members of the association and the college of cardiology held a hastily called closed-door meeting with Dr. Ridker, who directs the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston. He showed them his data and pointed out the problem. On Sunday, officials from the organizations struggled with how to respond.
Other experts said there has not been a real appreciation of the difficulties with this and other risk calculators. "I don't think people have a good idea of what needs to be done," said Dr. Michael Blaha, director of clinical research at the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins University, who was not associated with forming the new guidelines.
Dr. Blaha said the problem might have stemmed from the fact that the calculator uses as reference points data collected more than a decade ago, when more people smoked and had strokes and heart attacks earlier in life. For example, the guideline makers used data from studies in the 1990s to determine how various risk factors like cholesterol levels and blood pressure led to actual heart attacks and strokes over a decade of observation.
But people have changed in the past few decades, Dr. Blaha said. Among other things, there is no longer such a big gap between women's risks and those of men at a given age. And people get heart attacks and strokes at older ages.
"The cohorts were from a different era," Dr. Blaha said.
This week, after they saw the guidelines and the calculator, Dr. Ridker and Dr. Cook evaluated it using three large studies that involved thousands of people and continued for at least a decade. They knew the subjects' characteristics at the start - their ages, whether they smoked, their cholesterol levels, their blood pressures. Then they asked how many had heart attacks or strokes in the next 10 years and how many would the risk calculator predict.
The answer was that the calculator overpredicted risk by 75 to 150 percent, depending on the population. A man whose risk was 4 percent, for example, might show up as having an 8 percent risk. With a 4 percent risk, he would not warrant treatment - the guidelines that say treatment is advised for those with at least a 7.5 percent risk and that treatment can be considered for those whose risk is 5 percent.
"Miscalibration to this extent should be reconciled and addressed before these new prediction models are widely implemented," Dr. Ridker and Dr. Cook wrote in The Lancet. "If real, such systematic overestimation of risk will lead to considerable overprescription."
In a response on Sunday, Dr. Smith of the guidelines committee said the concerns raised by Dr. Cook and Dr. Ridker "merit attention."
But, he continued, "a lot of people put a lot of thought into how can we identify people who can benefit from therapy." Further, said Dr. Smith, who is also a professor of medicine at the University of North Carolina and a past president of the American Heart Association, "What we have come forward with represents the best efforts of people who have been working for five years."
The chairmen of the guidelines panel said they believed the three populations Dr. Ridker and Dr. Cook examined were unusually healthy and so their heart attack and stroke rates might be lower than expected.
Asked to comment on the situation on Sunday, some doctors said they worried that, with many people already leery of statins, the public would lose its trust in the guidelines or the heart associations.
"We're surrounded by a real disaster in terms of credibility," said Dr. Peter Libby, the chairman of the department of cardiovascular medicine at Brigham and Women's Hospital.
What are patients and doctors to do? On Sunday, there seemed to be no firm answers, except that those at the highest risk, like people who have had a heart attack or have diabetes, should take statins.
The guideline developers said they were not totally surprised by the problems with the calculator.
"We recognize a potential for overestimates, especially at the high end of risk," said Dr. David Goff, the dean of the University of Colorado School of Public Health and the co-chairman of the guidelines' risk assessment working group.
Last year, not long after it received the assessments from Dr. Ridker and Dr. Cook, the National Heart, Lung and Blood Institute removed itself from the development of the guidelines, saying that was not its mission. The institute handed responsibility to the American Heart Association and the American College of Cardiology.
Dr. Michael Lauer, the director of the division of cardiovascular sciences at the institute, said on Sunday that it had received many reviews and sent them to the other groups, together with the responses of the guidelines' authors.
Some doctors who tested the calculator with hypothetical patients wondered if they should trust the results.
Dr. Nissen entered the figures for a 60-year-old African-American man with no risk factors - total cholesterol of 150, HDL (the good cholesterol) of 45, systolic blood pressure of 125 - who was not a diabetic or a smoker. He ended up with a 10-year risk of 7.5 percent, meaning he should be taking cholesterol-lowering statins despite being in a seemingly low-risk group.
Dr. Nissen also calculated the figures for a healthy white man, age 60, and also got a risk factor of 7.5 percent.
"Something is terribly wrong," Dr. Nissen said. Using the calculator's results, he said, "your average healthy Joe gets treated, virtually every African-American man over 65 gets treated."
February 5, 2014
More Than a Billion People Taking Statins? Potential Implications of the New Cardiovascular Guidelines
John P. A. Ioannidis, MD, DSc1,2
The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on assessment of cardiovascular risk1 and on treatment of blood cholesterol, which included recommendations for primary prevention with statins,2 came under intense criticism immediately with their release. Main concerns focused on flawed methods (problems with the risk calculation),3 ethics (conflicts of interest),4 and inferences (too many people offered treatment).
The ACC and the AHA are among the most experienced organizations in medicine that develop guidelines. Their processes are meticulous, including transparent reporting of conflicts. The work behind the guidelines' development was monumental. References to randomized trials and systematic reviews were continuous (the word "evidence" appears 346 times in the cardiovascular risk assessment report and 522 times in the treatment report alone). Panelists were highly qualified. Statins have been extensively evaluated in numerous randomized clinical trials. The guidelines focused on hard clinical outcomes such as myocardial infarction and stroke. Remaining caveats were explicitly acknowledged in documents covering hundreds of pages. However, this apparently seasoned integration of data and opinion eventually would lead to massive use of statins at the population level; ie, "statinization." It is uncertain whether this would be one of the greatest achievements or one of the worst disasters of medical history.
According to the ACC/AHA guidelines1,2 of the 101 million people in the US population without cardiovascular disease and aged 40 to 79 years, 33 million are expected to have a 10-year predicted risk of cardiovascular disease of 7.5% or higher (ie, high-intensity statins are recommended) and another 13 million are expected to have a predicted risk between 5% and 7.4% (ie, statins should be considered). The US population is approximately one-twentieth of the global population in this age range. If crude distributions of risk profiles were similar, on average, around the globe, a rough estimate would suggest that (33 + 13) × 20 = 920 million people would be classified in the same risk categories. This is probably an underestimate. Accounting for population growth, an increasingly aging population in developed countries, and increasing prevalence of cardiovascular risk factors in developing countries resulting in risk profiles worse than that of the United States,5 these risk categories may already exceed or could soon exceed 1 billion people. These projections do not even count the hundreds of millions of patients who already have cardiovascular disease or extremely high low-density lipoprotein cholesterol levels and for whom statins demonstrate even better effectiveness.
Risk profiles and the importance of risk factors may well differ in other populations, and the ACC/AHA guidelines are very careful in avoiding such extrapolations.1However, unavoidably, extrapolations will happen. Prior experience shows that previous efforts such as the Framingham risk score and the Third Adult Treatment Panel (ATP III) guidelines were adapted and adopted widely around the world. Authoritative guidelines of this sort carry such prestige that they influence global treatment and marketing. Moreover, several statins are available as generic products and are relatively inexpensive, contributing to further pressure to "statinize" the planet even in countries with modest health care budgets.
The core of the ACC/AHA guidelines depends on a new risk score that was explicitly developed for the sake of informing US-oriented recommendations. Problems with this score have been noted,3 and even its developers largely acknowledged them up front.1 Based on the evidence of overprediction derived even in the original validation of the risk calculator and subsequent independent validations, perhaps about half of statin candidates may actually have a true 10-year risk of less than 7.5%.1,3 However, there is large uncertainty about the extent of any overprediction, and the cohorts in which the model was developed and validated may differ compared with current populations. Here, several important factors must be considered. First, after 30 years of work and hundreds of cardiovascular predictors and models,6 when the time came, the expert panel considered (probably correctly) that none of the models previously developed was good enough and had to develop a new one. Second, despite a plethora of candidate emerging predictors of cardiovascular risk, the model ended up selecting risk factors known since the 1960s: age, sex, race, lipids, diabetes, smoking, and blood pressure. Third, when looking at the granularity of the predictors (eg, how lipids should be represented), high-density lipoprotein cholesterol was selected even though it is clearly noncausally related to coronary artery disease,7 an example of how highly significant predictors may have little to do with how treatment works. Fourth, even the new model was acknowledged by its developers as having major limitations.1 Performance in external validation cohorts is clearly disappointing. Areas under the curve range from 0.56 to 0.71 (except for African American women) and calibration metrics (χ2 of 15 to 67) are worse than almost any previously published cardiovascular model.6 The development of the new model most likely was rigorous, and these disappointing numbers are an accurate reflection of its performance. But what does this say about the credibility of all the other previous models that seemingly have superior (published) performance? It is concerning that after thousands of articles on cardiovascular prediction, this is the best that can be expected. Fifth, even though many randomized trials on statins have been published, there is no randomized evidence that this particular risk model, rather than any of its predecessors built with the same, similar, or other predictors, would identify the patients who benefit most from statin therapy and that the optimal treatment threshold is 5%, 7.5%, or even 2.5% or 15%. Information on potential statin harms (myopathy, diabetes, and more) is accumulating and concerning but also less systematically collected and thus carries more uncertainty than the benefits. The exact incidence of harms could markedly affect the optimal risk threshold for treatment.
Eventually, a leap of trust is needed to interpret clinically this excellent but convoluted and problematic modeling effort and its management implications-this was left to the otherwise excellent content experts who made the influential treatment recommendations. So, here, critics point out that 8 of the 15 panelists had industry ties.4 Perhaps this is an improvement because almost all panelists who participated in the prior ATP III guidelines had industry ties. Moreover, the new guidelines often recommend more inexpensive therapies. However, should the very best content experts be the ones writing recommendations, making that delicate leap from the often fragmented or uncertain evidence to the actual dicta? Can the very best content experts ever be conflict free?8 Critics have justifiably pointed out4 that severing ties with the industry while working on the guidelines and promising not to have any industry ties for at least 2 years after the guidelines are published does not abolish conflicts. Even if all expert panelists have no financial industry ties, the decisions they make may affect how many patients will visit preventive cardiology clinics and influence patient activity in these divisions. The debate over the ACC/AHA guidelines offers an opportunity to rethink the membership of these influential panels. As articulated by the American Cancer Society and as recommended by the Institute of Medicine, the American Cancer Society will separate the processes of specialty input and evidence synthesis from writing of the actual guideline.9 Perhaps these panels should include knowledgeable patients who are well versed in understanding the scientific background (eg, predictive models), many methodologists (ideally working in different applied fields), and excellent clinicians/scientists from other specialties whose practice volume is not at stake. Content experts could serve as nonvoting members or advisors to such panels.
The ACC/AHA guidelines demonstrate that even in a topic area with extensive amounts of data and published clinical trials, crucial evidence is still missing. The definitive way to test the recommendations is to subject them to randomized experimentation. The new proposed model could be compared against other models or approaches in its ability not only to predict risk accurately but also affect patient outcomes.8 The proposed strategy could also be compared against different strategies where treatment is recommended at different thresholds. With potentially more than 1 billion people caught in the statin dilemma, there should be hundreds of thousands of interested participants for such trials. With expanded target populations and more affordable generic prices, the cumulative global sales of statins may approach $1 trillion by 2020. Lipitor sales alone exceeded $120 billion between 1996 and 2011. Therefore, funding for trials to demonstrate the best predictive model and treatment threshold should be negligible compared with the accumulated profit from statins and the millions of lives and deaths at stake.