Millions Of Americans Taking Aspirin When They Shouldn’t Reply

More than a third of US adults– more than 50 million people– now take aspirin for the primary and secondary prevention of cardiovascular disease. (Primary prevention is the prevention of a first event; secondary prevention is the prevention of a recurrent event.) Although it was once broadly recommended, because of the increased risk of bleeding complications the use of aspirin for primary prevention of cardiovascular disease is now only indicated in people who have a moderate to high 10-year risk. (Aspirin is still broadly recommended for secondary prevention.) Now a new report  published in the Journal of the American College of Cardiology finds that there are still a significant number of people who are receiving aspirin inappropriately.

Click here to read the full post on Forbes.



Large Japanese Trial Casts Further Doubt On Aspirin To Prevent A First Heart Attack Reply

Although once quite popular, the use of aspirin to prevent a first heart attack has grown less popular in recent years as evidence has accumulated that the small benefits are outweighed by the increased risk of bleeding. Now a large trial from Japan has once again failed to provide any evidence to support the use of routine aspirin in high risk elderly people to prevent a first cardiovascular event.

The Japanese Primary Prevention Project (JPPP),  presented at the American Heart Association meeting in Chicago and published simultaneously in JAMA, enrolled  patients between 60 and 85 years of age with  hypertension, dyslipidemia, or diabetes. The open label study randomized 14,464 patients to aspirin 100 mg once daily or no aspirin in addition to conventional therapy. Patients were followed for up to 6.5 years for the primary combined endpoint of cardiovascular death, nonfatal stroke, or nonfatal MI….

Click here to read the full post on Forbes.


BMJ Articles Critical Of Statins Provoke Kerfuffle Reply

The authors of two BMJ articles have withdrawn statements about the adverse effects of statins. The two papers inaccurately cite an earlier publication and therefore overstate the incidence of adverse effects of statins. As a result, the two papers have drawn much criticism and set off a kerfuffle involving the editor of BMJ and a prominent British trialist who is demanding a full retraction of the articles. But the controversy probably won’t be resolved any time soon, since an independent panel, which will be asked to decide the issue, is still in the process of being assembled.

Click here to read the entire post on Forbes.


FDA Comes Out Against Aspirin To Prevent First Heart Attacks 1

In the latest development in a long-simmering debate, the FDA has announced that aspirin should not be marketed for the prevention of a first heart attack or stroke in people with no history of cardiovascular disease. The announcement follows FDA’s rejection on Friday of Bayer Healthcare’s decade-old  petition requesting approval of a primary prevention indication. [PDF of FDA rejection letter]

Click here to read the full post on Forbes.


Reassuring News About Statins From Two Very Different Studies Reply

Although clinical trials have consistently demonstrated the benefits of statins, the perception that the drugs can cause serious side effects has prompted some patients to discontinue or not take the drugs. Now two new very different studies, one a large meta-analysis and one a tiny study with only a handful of patients, provide some convincing reassurance that most of the side effects that have been tied to statins do not appear to be actually caused by the drugs.

Click here to read the full post on Forbes.


Low Rate Of Problems With Statins In Study Of Quarter Million Patients 1

A very large analysis of previously published studies finds that statins are generally safe and well tolerated, but helps confirm previous links to a small increased risk for diabetes and elevation of liver enzymes. Some statins were better tolerated than other statins and lower-dose statins were better tolerated than high dose statins.

In a paper published in Circulation: Cardiovascular Quality and OutcomesHuseyin Naci and colleagues report their findings from a systematic review of clinical trials with statins for both primary and secondary prevention. The data from 55 placebo controlled trials and 80 trials included nearly 250,000 subjects comparing statins to placebo or to other statins. Previous analyses of available data have generally confirmed the overall benign profile of statins, but have not explored in depth the differences between statins and the effect of different doses of individual statins.

The new study found no differences between statins and placebos in the rate of discontinuations due to myalgia, CK elevation and cancer, but statins were associated with a higher risk for diabetes (OR 1.09, CI 1.02-1.16) and transaminase elevations (OR 1.51, CI 1.24-1.84).

Click here to read the full post on Forbes.


UK Study Casts Doubts On Value Of Type 2 Diabetes Screening Reply

The dramatic growth in type 2 diabetes has resulted in increased interest in screening programs. Now a new study published in the Lancet raises concerns that screening programs may not result in long-term improvement in outcomes.

In the ADDITION-Cambridge study, investigators in the UK randomized general practices to either screening or no screening.  The practices allocated to screening were further divided to either intensive cardiovascular risk reduction or standard care. The study population included more than 20,000 adults 40-69 years of age at high risk for undiagnosed diabetes.

3% of patients in the screening groups received a diagnosis of diabetes. After a median followup of 9.6 years, there were no significant differences between the screened population and the control group.

Rate per 1,000 person-years and hazard ratios for the no-screening and the screening group:

  • Mortality: 9.89 versus 10.50, 1.06 (CI 0.90-1.25)
  • CV mortality: 3.25 versus 3.30, 1.02 (0.75-1.38)

The authors proposed several explanations for the lack of benefit associated withs screening, including ad-hoc screening outside the practice setting in the unscreened group, patients who did not follow the screening program, and concurrent gains in identifying and managing other cardiovascular risk factors during the study period. In addition, the patient population in the study may have been a relatively healthy population with a lower prevalence of undiagnosed diabetes.

The authors concluded that “if population-based screening for diabetes is to be implemented, it should be undertaken alongside assessment and management of risk factors for diabetes and cardiovascular disease and population level preventive strategies targeting underlying determinants of these diseases.”

In a Lancet press release, senior author Simon Griffin said that “the benefits of screening might be smaller than expected and restricted to individuals with detectable disease.  However, benefits to the population could be increased by including the detection and management of cardiovascular risk factors alongside the assessment of diabetes risk, performing repeated rounds of screening, and improving strategies to maximize the uptake of screening.”

In an accompanying comment, Michael Engelgau and Edward W Gregg write that prevention programs should screen not just for diabetes but for high-risk individuals as well, though they note that this strategy “assumes that effective prevention programs are available to high-risk cases.” Further, the value of screening depends “on more than just mortality as an outcome,” and will need to include morbidity, quality of life, and costs.
Click here to read the Lancet press release…

Real World Bleeding Risk Of Aspirin In Primary Prevention Examined Reply

A new study published in JAMA provides substantial new evidence about the real world effects of aspirin, including the risk of  bleeding, in a broad  population. The study also sheds important new light on the effects of aspirin in a diabetic population.

Giorgia De Berardis and colleagues analyzed data from more than 4 million people in Puglia, Italy and compared 186,425 people taking low-dose aspirin with the same number of matched controls not taking aspirin.

Major bleeding events requiring hospitalization:

  • aspirin: 5.58 (5.39-5.77) per 1000 person-years
  • controls: 3.60 ( 3.48-3.72) per 1000 person-years
  • Incidence rate ratio (IRR) 1.55 (1.48-1.63)

Diabetics overall had an increased risk of major bleeding episodes but this increased risk was not significantly associated with aspirin use:

  • Hemorrhagic events in diabetics overall (compared with non diabetics): IRR 1.36 (1.28-1.44)
  • Hemorrhagic events in diabetics taking aspirin compared with diabetics not taking aspirin: IRR 1.09 (0.97-1.22)

The authors wrote that their findings demonstrate that bleeding events occur more frequently than had been observed in clinical trials. They calculated that for individuals with a 10-year risk of cardiovascular events between 10% and 20% the risks and benefits of aspirin therapy are similar, causing 2 excess bleeds, and preventing 2 CV events, for every 1,000 people treated each year.

In an accompanying editorial, Jolanta Siller-Matula writes that the benefits of aspirin in secondary prevention are “not disputed,” since aspirin can prevent 6 major vascular events at the expense of 1 major bleeding event. But there is no such consensus for primary prevention, and Siller-Matula writes that the findings of the Italian study reinforce current European guidelines which do not recommend aspirin for primary prevention.

The JAMA study provides far more information about aspirin use in diabetics than had been previously available. Nevertheless, writes Siller-Matural, the decision whether to use aspirin for primary prevention in this population is still not clear, and will require additional data from ongoing studies.

Click here to read the JAMA press release…

Fascinating Debate Over Statins For Primary Prevention 2

The recent guest post by David Newman has prompted several thought-provoking comments. Since most readers will likely miss the comments, I’ve moved these comments to a separate post.

Statin Island May 27, 2012, 3:35 PM:

Thank you. Clearly, this important commentary raises questions about the integrity of Lancet as well as the authors of the study.

But what is most discouraging, and dangerous, is that this kind of deception occurs so frequently. Meanwhile, major news outlets, television channels, etc. have reported the results as the authors intended. And so the gravy train has left the station.

Lancet should publish a clarifying editorial and send it everywhere they can. They are an accessory to any harm that has resulted, to patients and to the credibility of medical science.

Michael V Holmes (@mvholmes) (May 28, 2012, 10:10 AM:

I disagree with this critique. The authors weighed each RCT by the LDL-C lowering to be able to provide a standardized comparison across the studies (it’s in the Methods of the paper). By doing so, they didn’t break the randomization, and shouldn’t have introduced confounding, as suggested by this commentary piece. And being able to say “for each 1 mmol/L LDL-C reduced, the RR of CHD is 0.79, 95% CI 0.77, 0.81″ is very helpful metric.

Larry Husten (May 28, 2012, 12:31 PM:

I don’t claim to be an expert in meta-analysis but I’m not sure that Holmes is responding to the fundamental flaw in logic in the Lancet paper raised by Newman. The Lancet paper– correctly, as Newman acknowledges– identifies a benefit for statins in people who respond to statins, but it says nothing about the broader primary prevention population, some of whom will not respond to statins. The conclusion reached by the CTT authors, that statins should be more widely used in this primary population, is therefore unwarranted.

I am hopeful that Dr. Newman will respond in more detail and discuss the technical issues raised by Holmes.

MDinSTL (May 30, 2012, 11:32 AM):

Within any randomized group, some will do better than others. When targeting a lower LDL, those who achieve and maintain the target do better than those who do not. This phenomenon has been called dose targeting bias.

What is key to understand though is that an intervention may have NO benefit, yet this relationship of better LDL lowering to better outcomes can still be observed.

Therefore if the trials show no net benefit between statin vs placebo, it is not necessarily true that the subgroup analysis the Lancet group employs means some people benefited.

This is easiest to see by considering this point: If the statin-treated non-CAD patients had no overall reduction in mortality, and the subgroup with a large LDL drop did have lower mortality, then those without a large LDL drop must have been harmed by statins to account for the lack of overall effect compared to the placebo-treated patients.

If investigators really believe some benefit from statins accrues to those without apparent CAD provided LDL falls at least 40 pts, then the answer is to perform a trial where entry criteria include an ability to show a 40 pt drop in LDL, then randomize pts to statin vs no statin. That ain’t gonna happen because 1. few seriously believe that, and 2. this message is really a marketing message intended to promote use of statins in the general population.

DH Newman(May 28, 2012, 5:08 PM: 
Click to continue reading…

Guest Post: Data, Drugs, And Deception– A True Story 15

Editor’s Note: The following guest post by Dr. David Newman is reprinted with permission from his website and blog, Smartem.Org. Dr. Newman is an Emergency Physician and Director of Clinical Research at Mt. Sinai School of Medicine in the Department of Emergency Medicine.  He is the author of the critically-acclaimed Hippocrates’ Shadow: Secrets From the House of Medicine. CardioBrief readers might also enjoy watching his TED talk, Truth That Lasts.

Data, Drugs, And Deception– A True Story

by Dr. David Newman

Last week The Lancet published a meta-analysis of 27 statin trials, an attempt to determine whether patients with no history of heart problems benefit from the drugs — true story. The topic is controversial, and no less than six conflicting meta-analyses have been performed — also a true story. But last week’s study claims to show, once and for all, that for these very low risk patients, statins save lives — true story.

Actual true story: the conclusions of this study are neither novel nor valid.

The Lancet meta-analysis, authored by the Cholesterol Treatment Trialists group, examines individual patient data from 27 statin studies. Their findings disagree with an analysis published in 2010 in theArchives of Internal Medicine, and with analyses from two equally respected publications, theTherapeutics Letter and the Cochrane Collaboration.* Despite this history of dueling data the authors of last week’s meta-analysis, in a remarkable break from scientific decorum, conclude their report with a directive for the writers of statin guidelines: the drugs should be broadly recommended based on the new analysis.

As an editorialist points out, if implemented, the CTT group recommendations in the United States would lead to 64 million people, more than half of the population over the age of 35, being started on statin therapy — true story.

Where is the magic, you ask, in this latest effort? What is different? In some ways, nothing. Indeed just a year and a half earlier The Lancet published a meta-analysis of 26 of the same 27 studies, with the same results, by the same authors (true story, and an odd choice on the part of the journal). So the findings aren’t new. They are, however, at odds with other meta-analyses. Why? It is the way they calculated their numbers. This meta-analysis, like the earlier one from the same group, reports outcomes per-cholesterol-reduction. The unit they use is a “1 mmol/L reduction in low density lipoprotein (LDL)”, in common U.S. terms, a roughly 40-point drop in LDL.

That’s the magic: each of the benefits reported in the paper refers to patients with a 40-point cholesterol drop. Voilá. One can immediately see why these numbers would look different than numbers from reviews that asked a more basic question: did people who took statins die less often than people taking a placebo? (The only important question.) Instead, they shifted the data so that their numbers corresponded precisely to patients whose cholesterol responded perfectly.

Patients whose cholesterol drops 40 points are different than others, and not just because their body had an ideal response to the drug. They may also be taking the drug more regularly, and more motivated. Or they may be exercising more, or eating right, and more health conscious than other patients. So it should be no surprise that this analysis comes up with different numbers than a simple comparison of statins versus placebo pills. Ultimately, then, this new information tells us little or nothing about the benefits someone might expect if they take a statin. Instead it tells us the average benefits among those who had a 40-point drop in LDL.
Click to continue reading…

Meta-Analysis Adds New Evidence For Cancer Benefits Of Daily Aspirin 1

Although daily aspirin was originally proposed to reduce cardiovascular events, the effects on cancer of daily aspirin have become increasingly apparent while the vascular benefits, especially in primary prevention, have become less clear. Now a new meta-analysis in the Lancet adds significantly new details to our understanding about the effects of aspirin and increases the evidence in support of a long-term beneficial effect of aspirin in preventing cancer.

Peter Rothwell and colleagues analyzed data from 51 primary and secondary prevention trials including more than 80,000 patients. They reported several key findings

  • Daily aspirin reduced deaths from cancer by 15% (p=0·008).
  • After 5 years, there was a particularly striking 37% reduction in cancer deaths (p=0·0005), which largely accounted for a reduction in non-vascular deaths overall (p=0·003).
  • Aspirin was associated with an initial reduction in major vascular events, but this was offset by increases in major bleeding. With longer followup the vascular effects diminished, so that after 3 years only the reduced risk of cancer was significant.

The authors wrote that “in view of the very low rates of vascular events in recent and ongoing trials of aspirin in primary prevention, prevention of cancer could become the main justification for aspirin use in this setting…”

In an accompanying comment, Andrew Chan and Nancy Cook point out that the meta-analysis did not include the two largest primary prevention studies, the Women’s Health Study and the Physician’s Health Study, because they used alternate-day aspirin rather than daily aspirin. Both trials failed to find an effect on cancer. Nevertheless, they write, the researchers “show quite convincingly that aspirin seems to reduce cancer incidence and death across different subgroups and cancer sites, with an apparent delayed effect.”

“For most individuals, the risk-benefit calculus of aspirin seems to favour aspirin’s long-term anticancer benefit,” they state. However, current evidence does not support “a definitive conclusion about population-based recommendations regarding routine use of aspirin for cancer prevention.” They conclude that in the future guidelines “can no longer consider the use of aspirin for the prevention of vascular disease in isolation from cancer prevention.”
Click here to read the press release from the Lancet…

Guest Post: Another Round in the Debate on Diabetes and Statins 4

Another Round in the Debate on Diabetes and Statins

by Roger Blumenthal

Let me start by saying that I am proud to have Eric Topol as a friend and a trusted advisor over the past 20 years. His work has been an inspiration to cardiovascular health professionals for several decades. His new book, The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care, should be required reading by all physicians and in all medical schools. It is simply that good.

Eric is a strong believer that we need to have more personalized medicine. I agree. I predict that he and his research group will lead the way to help us understand why certain people benefit more from certain medications and others may not. So far, the only ways we have to decide which asymptomatic persons would benefit from statin therapy are the traditional risk factors which make up the Framingham risk score, hsCRP, and coronary calcium measurements. Both of the latter two tests have been given a class IIa indication from the AHA for use in intermediate risk adults (Framingham score of 10-20% risk of an MI over the next decade.)

Eric is concerned about the apparent increased risk of diabetes with statin use. A 2010 meta-analysis in the Lancet found about a 10% increased risk in statin users. Eric rightly points out that the relative risk was higher with the more potent rosuvastatin in JUPITER. Yet, that is where we saw a  significant decrease in total mortality and the largest relative risk reduction in CVD events.
Click to continue reading…

Eric Topol, Megamind 2

Ralph Waldo Emerson famously wrote that “a foolish consistency is the hobgoblin of little minds.” If this is true then Eric Topol, who earlier today wrote a New York Times editorial highly critical of statins, is Megamind.

Here’s what he wrote in a 2004 editorial in the New England Journal of Medicine:

Even today, only a fraction of the patients who should be treated with a statin are actually receiving such therapy. It is estimated on the basis of the criteria in current national guidelines that 36 million people in the United States should be taking a statin, but only 11 million are currently being treated. Worldwide, the discrepancy is even more staggering; more than 200 million people meet the criteria for treatment, but fewer than 25 million take statins.

There will soon be a sea change in the prevention and management of atherosclerotic vascular disease. The proportional reduction in major clinical outcomes that results from aggressive statin therapy is of the same order of magnitude as that seen when statins were compared with placebo in controlled trials. Intensive therapy with statins, monitored by means of measurements of LDL cholesterol or biologic markers of inflammation, is likely to result in even greater steps toward actualizing the full benefit of this remarkable class of medicines.

To be fair, I think Topol deserves credit for being willing to change his mind. It’s a rare trait. But I’m not sure that every single current controversy in medicine should be seen in the light of a crusade in favor of genomics, so when a cardiologist with a long memory sent me this editorial I couldn’t resist posting this blast from the past.

Update: In all fairness, here is Dr. Topol’s response to the above post:

The op-ed on the risk of diabetes from statins had nothing to do with changing my mind. It has everything to do with new data that were not available in 2004. As I pointed out in the Times op-ed, the diabetes issue only surfaced in recent trials with higher doses (40 mg of Simvastatin) and atorvastatin (Lipitor) and rosuvastatin (Crestor). Prior to these trials, there was no signal about the risk of diabetes. The trial my NEJM editorial was written on in 2004–PROVE IT–showed no difference in diabetes for intensive vs moderate statins (5.9% in both groups). All of the subsequent intensive statin randomized trials–TNT, IDEAL, SEARCH showed an important excess. Even folding PROVE-IT to the mix, collectively the excess of an absolute 0.8% equates to developing diabetes in 1 of every 125 patients treated with intensive statins compared with moderate dose statins.

JUPITER, one of the largest trial of statins, with 17,802 patients, was not published until 2008, nor did we have diabetes data available from many of the other placebo-controlled trials until after 2004.The initial HPS trial primary report published in 2002 did not even mention the diabetes risk, which only came out much later!

Furthermore, this is not a crusade about genomics, which is a baseless point. This op-ed was aimed at consumers, who have every right to know the real data, the real risks and benefit of primary prevention with potent statins. The fact that we are in 2012, and have recognized the problem of statins engendering diabetes for the past 4-5 years, have no clue for why it occurs, and that nothing has been done about it in the medical community or by the life science industry, is truly remarkable.
Finally the author of this blog and I have a history of working together for many years on — as a journalist he should recuse himself of writing on this subject with clearcut evidence of bias.



Statins and Diabetes: Real Concern or Much Ado About Nothing? 6

Updated at 7 PM with a detailed comment at the bottom from C. Michael Minder of Johns Hopkins–

In New York Times Op-Ed piece on Monday, Eric Topol comments on last week’s announcement by the FDA that it was changing the label for statins. Topol focuses on the new warning that statins raise the risk of diabetes. He opens with a provocative statement:

We’re overdosing on cholesterol-lowering statins, and the consequence could be a sharp increase in the incidence of Type 2 diabetes.

Topol does the math and calculates that 20 million Americans taking statins equates to 100,000 new statin-induced diabetics:

Not a good thing for the public health and certainly not good for the individual affected with a new serious chronic illness… If there were a major suppression of heart attacks or strokes or deaths, that might be justified. But in patients who have never had heart disease and are taking statins to lower their risk (so-called primary prevention), the reduction of heart attacks and other major events is only 2 per 100. And we don’t know who the 2 per 100 patients are who benefit or the one per 200 who will get diabetes! Moreover, the margin of benefit to risk is quite narrow.

Topol then concludes that statins are beneficial for secondary prevention in people with a history of heart disease or stroke but for “the vast majority of people who take statins — those who have never had any heart disease — there should be a careful review of whether the statin is necessary, in light of the risk of diabetes and the relatively small benefit that can be derived.”
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Metaanalysis Raises More Questions About Routine Use of Aspirin for Primary Prevention Reply

Although aspirin can reduce the risk of cardiovascular (CV) events, the associated increase in bleeding suggests that it should not be used routinely in  people without prior CV disease, say the authors of a new meta-analysis published in Archives of Internal Medicine.

Sreenivasa Rao Kondapally Seshasai and colleagues combined data from 9 clinical studies including more than 100,000 participants who were followed for a mean of 6 years. They found a significant reduction in CV events, but not CV mortality, and an increased risk of important bleeding events:
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Rita Redberg and Roger Blumenthal Clash Over Statins for Primary Prevention in the Wall Street Journal 8

The debate over whether statins should be used for primary prevention moved to the Wall Street Journal with opposing perspectives from cardiologists Roger Blumenthal and Rita Redberg.

Blumenthal argues that “there is a mountain of high-quality scientific evidence” to support the use of statins in people without known heart disease but “demonstrated to be at high risk for heart disease.”

Redberg argues that “for most healthy people, data show that statins do not prevent heart disease, nor extend life or improve quality of life. And they come with considerable side effects. That’s why I don’t recommend giving statins to healthy people, even those with higher cholesterol.”
Click to continue reading…

Study Examines Changes in Resting Heart Rate Over Time 1

Although resting heart rate (RHR) has been long known to be associated with cardiovascular risk, change in RHR over time has not been well studied. A new paper from Norway published in JAMA demonstrates that an increase in RHR over 10 years helps predict the risk of all-cause and ischemic heart disease (IHD) death.

Javaid Nauman and colleagues analyzed data from 46,410 Norwegian adults without known cardiovascular disease who had their RHR measured at baseline and at 10 years.

IHD Mortality and Adjusted Hazard Ratios (AHR):
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