A recent meta-analysis in bmj of the treatment of people with multiple risk factors for heart disease but without a history of heart attacks looked at 70,388 people. They reported a 12% reduction in overall mortality which was statistically significant.

OK, so far so good.

However there are a number of problems with the conclusions not to mention the multiple pharma conflicts of many of the authors that may have contributed to those distorted conclusions.

In the conclusion section, they incredibly report a 12% reduction in mortality with no mention of differences by sex or diabetes status. They go on to write ”no significant treatment heterogeneity was found between the sexes, in elderly and young people, and between people with and without diabetes.” However inspection of Table 3 shows that there were in fact no statistically significan reductions any endpoint (mortality, heart attacks) in women or diabetics or people over age 65. Furthermore, there was no mention of number needed to treat (NNT), or the fact the number of people saved from a heart attack were not greater than those developed liver problems or severe musle pain (which could lead to rhabdomylosis, possibly fatal). Or that the 12% relative reduction is equal to about a 1% absolute reduction.

This misrepresentation of the results is bordering on fraudulent.

I just found a way to save 25 billion dollars a year for President Barack Obama’s healthcare plans. That is to cut out angioplasty (currently called percutaneous coronary intervention, or PCI), for which multiple studies, including one in the June 11 edition of the New England Journal of Medicine, show are not useful for patients with stable coronary artery disease (CAD). The mounting evidence that angioplasty is not more effective than medication treatment alone in preventing heart attack and death in people with stable heart disease doesn’t stop doctors from performing them.

In this procedure doctors put in a guideline in the coronary arteries and blow up a balloon that flattens plaque against the wall of the artery and opens up the artery or they insert a stent to keep the artery open. Sound good and makes sense, too bad it doesn’t work.

“There are people in the cardiology community who don’t believe the results. They don’t believe it applies to the patients they see,” Dr. Judith S. Hochman, director of the Cardiovascular Clinical Research Center at New York University School of Medicine, was quoted as saying. “So we still see a lot of angioplasty being done without patients really understanding that it will not reduce their chances of heart attack or death.”

But I’ll give the reason why they still perform 1.2 million of these procedures every year. It is pretty simple really. Greed.

Nancy Nielsen MD, President of the AMA, opposes healthcare reform

Doctors always say things like they don’t believe the data, or that isn’t the way it is in my practice. Since they won’t believe in science, data or reality, maybe we should just play their game and use some wizadry to get them to do the right thing and stop doing these useless procedures.

When I count to 3 you will stop performing angioplasties

Or maybe one of the Obama guys should have some guts and stand up and say we’re not gonna pay for those things anymore.

[Update: see comments section for reference to acute coronary events where PCI has demonstrated efficacy and citation by Marilyn Mann which was made immediately after I posted this on June 25 which I assumed was sufficient for anyone reading this; that didn't stop a cardiologist in another blog from going on the attack and saying that since the COURAGE trial showed lack of efficacy in reducing heart attacks in stable coronary disease these procedures have declined. Even so they are still estimated to be about 1/3 which is too many and some cardiologist lately have gone to jail for performing PCI on people with little or no heart disease. So my initial statement that 25 billion dollars could be saved is not correct. It is more like, um, 8 billion.]

This from a recent continuing medical education (CME):

May 28, 2009 — Blood-pressure-lowering drugs should be offered to everyone, regardless of their blood pressure level, as a safeguard against coronary heart disease and stroke, researchers who conducted a meta-analysis of 147 randomized trials (comprising 958,000 people) conclude in the May 19 issue of BMJ.

I have heard of this before through Mrs. Bremner, as there was discussion at Emory and the CDC about creating a “polypill” that would be given to the entire population to prevent heart disease. When asked why interventions like diet and exercise couldn’t be tried first the response was “we tried that and it doesn’t work”.

Which just makes me wanna say…

Argggg!!!!!

Not the polypill! Please!

The authors of the BMJ meta analysis have previously advocated that everyone over age 55 should take the polypill, which would include a statin for lowering cholesterol, three anti hypertensive drugs at half dosage, aspirin, and folic acid. Given that questions have arisen about the capacity of statins and anti hypertensive drugs to induce depression, I think they should add Prozac to the polypill.

Anyhoo according to this meta-analysis of anti-hypertension trials, giving three antihypertensive drugs will lower risk of coronary heart disease (CHD) events by 22%. What’s more, it doesn’t matter if your blood pressure is “normal” down to 110/70, you still get the reduction in CHD events.

The CME goes on to quote the study authors:

“Guidelines on the use of blood-pressure-lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure,” write Drs Malcolm R Law and Nicholas Wald (Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, UK). “Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.”

“Whatever your blood pressure, you benefit from lowering it further,” Law told heartwire . “Everyone benefits from taking blood-pressure-lowering drugs. There is no one who does not benefit because their blood pressure is so-called normal.”

Ya gotta wonder about the logic of these guys. First of all aspirin has repeatedly been shown to be useless for the primary prevention of heart attacks in terms of its overall risk-benefit ratio. Second of all, statins do not reduce mortality in men without heart disease and are not beneficial at all for women without heart disease not to mention that they have side effects which can be pretty significant.

Hat tip to Rick Lippin MD

I have never been excited about things like taking aspirin to prevent heart attacks as I have written about before (”Should I Take Aspirin or Put a Gun to my Head?“), and this week there is an article in Lancet that pretty much sums things up for me. The authors combined data from six large trials including 95,000 people who did not have heart disease who were taking aspirin for the prevention of heart attacks.

Taking aspirin was associated with a reduction to 0·51% aspirin vs 0·57% control per year in vascular events like heart attacks, due mainly to a reduction in non-fatal heart attacks (0·18% vs 0·23% per year). There was no effect on stroke (0·20% vs 0·21% per year). There was also no difference in death rates from heart attacks and strokes (0·19% vs 0·19% per year). Aspirin increased major gastrointestinal and extracranial bleeds (0·10% vs 0·07% per year, p<0·0001).

The others concluded that taking aspirin for prevention is of “uncertain net value”. In other words, useless. The meager savings from heart attacks is outweighed by dangerous bleeds, and it doesn’t save your life, so why bother?

Mrs. Bremner and mine (and Mary Kelley) editorial on the famous JUPITER study (in which statin medications were used to prevent heart disease in healthy people who had an elevation of the marker of inflammation C Reactive Protein (CRP) which has been linked to heart disease risk) just came out here in the journal Circulation, in which we argue that the results of the study do not dictate that such large numbers of people should start taking statin drugs for the prevention of heart disease based on the marker of inflammation C-Reactive Protein (CRP). I mean CRP can go up with a number of things, like not exercising, or being overweight, etc. There was a response written by the lead author of JUPITER, Paul M. Ridker MD MPH which I read but cannot put online yet, which basically states that it was justified to stop the study early (which incidentally was used to hype the results of the trial) and that the apparent increase in markers of diabetes with statin treatment was not a big deal. I reprint the conclusion of our editorial here:

We believe that the treatment benefits achieved in the JUPITER trial are not large enough to advocate an expansion in the clinical indications for statins. The potential implications of this trial for a change in clinical practice are further limited by a lack of information on the long-term risks and benefits of statin therapy in predominantly healthy individuals. Unfortunately, it is unlikely that we will be able to gather these data in the future. Because sponsorship of major treatment trials is almost exclusively left to the pharmaceutical industry, it is doubtful that another trial will be carried out, with sufficient sample size and proper follow-up, to study the effects of statin treatment in such healthy individuals.

And we go on:

Perhaps the most important lesson to be learned from this trial is that extreme caution should be placed in deciding to terminate early an industry-sponsored trial, such as JUPITER. At the current status of knowledge, behavioral prevention strategies remain the best investment for the prevention of cardiovascular disease and its risk factors in predominantly healthy individuals.

Last week Mrs. Bremner was communicating to us from the American Heart Association Meeting about the importance of salt on blood pressure and health which led to a post about the topic which led to a lively discussion. David Colquhoun started out by pointing out that the graph showing a correlation between salt load and hypertension from the paper by Professor MacGregor could be accounted for by four data points. Mrs. Bremner countered by pointing out that they had re-analyzed the results without the four lowest data points and it was still significant. She subsequently pointed to another paper which summarizes clinical trials on the effects of salt reduction in the diet on health.

In this paper the authors point out that many studies that are used to argue that salt reduction has no effect on hypertension or health are studies in which the salt reduction only occurred of the course of one week, or involved acute salt depletion. The authors point out that one week is not long enough to evaluate the effects of salt reduction, and that acute salt reduction leads to an activation of the sympathetic nervous system, which leads to an artificial increase in blood pressure. Sounds good to me so far, guys.

They listed 17 trials of people with hypertension and 11 trials of people with normal blood pressure that were conducted for four weeks or more and had adequate salt reduction (4.6 g per day) as measured by excretion in the urine. People with hypertension had a 5 mm Hg point drop in systolic and 3 point drop in diastolic. People with normal blood pressure also showed a drop to a lesser extent. The authors note that this amount of salt reduction would result in a 14% drop in strokes and a 9% drop in heart deaths.

Clinical trials of dietary salt reduction and high blood pressure

Unfortunately noone has done a randomized trial of low salt versus high salt diet and it is unlikely to happen now due to ethical issues. Mrs. Bremner points out that increases in salt in the diet lead to a craving for salty food that causes a vicious cycle, which is one way people may become addicted to salty junk foods and snack foods.

Dr B.’s comment: It looks like cutting down on salt does lower blood pressure although a 14% relative reduction in cardiac events may not be that big of a deal in terms of absolute reduction of risk for a single individual. Salt may be just part of the problem with junk food. There was a study showing that people who eat in fast food restaurants three times a week have a greater than 90% risk of getting diabetes or heart disease and I need to find that reference again.

This week’s JAMA has an article that evaluates guidelines written for the appropriate treatment of a variety of cardiac conditions. These are guidelines written by experts in the field about appropriate treatments for a variety of conditions, from heart attacks to atrial fibrillation. The guidelines were ranked according to level of evidence, with guidelines ranked as A being based on multiple clinical trials, B based on a single study, and C based on expert opinion, “standard of care”, or case studies. The study showed that in 54% of cases, the guidelines were based on evidence ranked as C, in other words the personal opinions of whoever was writing the guidelines. The other finding was that the number of guidelines were increasing all the time, in spite of the fact that the evidence to support these opinions wasn’t.

In other words, about half the time someone is writing something and everyone else is supposed to go along. This is actually how medical education works; you see the professor prescribe in a certain way, and you do the same. Given the fact that the pharmaceutical industry has moved in and gotten control of leaders in their fields, through payments for consulting and lecturing, whom they derisively refer to as “KOLs” (Key Opinion Leaders), and whom pay consulting groups to “manage their KOLs”, you shouldn’t have much confidence in these guidelines, as I wrote about recently in “How Much You Gonna Pay Me for Those Guidelines.”

Dr Curt Furberg testifies before Congress regarding expert consensus guidelines

Hey! I think I came up with a better use for those guidelines!

A better use for expert consensus guidelines

This article just in from the Women’s Health Initiative Study, published in this month’s edition of the Archives of Internal Medicine, on the utility of taking multivitamins for postmenopausal women. Now since the marketing staff of the Drug Safety and Health News Blog have been conducting focus groups amongst the readers of the blog, we have learned that the average reader is a middle aged woman from Marin County CA with a family member with a history of heart disease and/or mental illness, who is concerned about developing osteoporosis, who has pondered over the utility of hormone replacement therapy, and who shops for organic foods and wants to put more fresh fruits and vegetables in her diet. That said, our readers should be interested in this post.

However, I am aware of the possibility that our readers have become attached to their multivitamins, having given up psychotropic drugs that they put high hopes in, but that turned to have more toxicity than therapy, or having flipped the bird at Sally Field and tossed their Boniva for osteoporosis prevention in the trash and turned to ‘natural’ vitamins and supplements instead. And since the Drug Safety and Health News has lost it’s advertising revenue from the pharmaceutical industry it is a bit going out on a limb risk losing it from the makers of vitamins and supplements as well. But any way (deep breath) here goes…

The study is from data from the Women’s Health Initiative, a large study conducted over many years on a range of health issues. The current article looked at 161,808 women with information collected on use of multivitamins over the course of eight years on average. There were no differences between women who did or did not take multivitamins in the risk of any type of cancer, heart attack or stroke. If anything the risk of death was increased by 2%, which was not statistically significant. Additionally, a report from last month from the Phyisicans Health Study, which reported on 14,641 male physicians over the age of 50, did not find any effect on any type of cancer or total mortality or heart disease with supplementation with vitamins C or E over the course of ten years.

I was watching public TV a couple of years ago when a researcher was being interviewed about the Beta Carotene and Retinol Efficacy Trial (CARET), in which 18,314 smokers took either beta carotene and Vitamin A or a placebo. He embarrassedly stated that the beta carotene (found in carrots and orange vegetables) and Vitamin, even though they are ‘anti-oxidant’ and theoretically should prevent heart disease and cancer, actually increased it in their trial.  In fact people on supplements equal to four carrots a day had 17% more heart disease and were 17% more likely to die than people on a placebo. People taking high doses of Vitamin A also doubled their risk of fracture, leading Denmark to ban vitamin fortified Kellogg’s breakfast cereals.Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study smokers treated with beta-carotene and alpha tocopherol (Vitamin E) had an 8% increase in death, while those with a prior history of heart attack had a 75% increase in heart attack with beta carotene therapy. People on Vitamin E had a 2% increase in mortality.all studies put together, there is an increased risk of heart disease with Vitamin A and beta carotene and no heart disease prevention with Vitamin E. Vitamin A and beta carotene when taken together are associated with a 29% increase in mortality.study of Vitamin E combined with Vitamin C showed that vitamins actually accelerated the progression of thickening of the coronary arteries, and doubled the risk of dying of heart disease. Another study of a combination of anti-oxidants, including Vitamins E, C, beta carotene, and selenium, showed that vitamins actually blocked the effects of anti-cholesterol treatment (simvastatin plus niacin) on reducing atherosclerosis and preventing heart attacks and strokes. The vitamins in this study interfered with the ability of the other medications to raise HDL (good) cholesterol. Looking at all studies combined in which Vitamin E was given with beta carotene, there was a 10% overall increase in mortality. So there it is (sigh).

I found that pretty surprising, given all the hype you hear about the benefits of anti-oxidant vitamins.

I later visited my sister-in-law Rossana (pronounced ROE – SSSS – ana, as my kids always point out) in the US Virgin Islands. Rumaging in her refrigerator while she was at work (hey I didn’t have anything else to do) I found several large bottles of vitamins and supplements. I looked at the ingredients and found that she was taking Vitamin A at several times the recommended daily levels. When she got home from work I confronted her about it.

Doug: “Rossana, why are you taking so many vitamins and supplements?”

Rossana: “I don’t have time to cook meals and eat enough vegetables, so this gives me what I need.”

Doug: “But did you realize that the amount of Vitamin A you are taking may cause osteoporosis?”

[It's true-- women taking the highest amounts of Vitamin A supplements

I don't want to be dodgy and name the company that made the vitamins and supplements she was taking, but I looked them up on the internet, and if you followed their recommendations, you would be spending $7,128 dollars per year on their products!

Even though in the laboratory there has been shown some connection between oxidative stress and heart disease, and in spite of the known role of vitamins C and E as anti-oxidants, you can't get around the fact that there is now a large body of research including studies with tens of thousands of patients that have shown that vitamins do not prevent heart disease or lengthen your life.

In fact, they may actually have the opposite effect.

I think the vitamins may be giving a boost to little tumors that wouldn't have been a problem otherwise.

I know the readers of this blog are going to protest and say they didn't use the right dose or right type of vitamins. But why don't you just get your vitamins from natural sources instead of a pill? And what about the conflicts of interest of those trying to sell you something? Here at Drug News and Health Safety we have been growing our own herbs and vegetables from seed. There is an added mental health benefit in helping the little parsley plants raise up their tired heads from the earth.

We can do it. Yes we can!

My daughter always wanted to take a pill when she wasn’t feeling well when she was a little girl, so my wife, after she had given her various cold remedies or whatever, would give her a pine nut. It was small, and tasty, and you could almost feel its beneficial effects.

For all you do, this (pine nut) pill is for you!

Kind of like obecalp, the fake medication sold to kids to make them feel better. See my post “Mommy Can I Have a Yummy Blue Pill?” Oh btw obecalp is placebo spelled backwards (I said that to make your head spin around like they did on the Exorcist).

Hat tip to Mrs. Bremner.

Bayer announced today that it is going to spend $20 million for an advertising campaign to reverse the effects of its ad campaign promoting the oral birth control pill, Yaz, as effective for the ups and downs of daily life as well as zits and other skin blemishes. This ad campaign was launched after Yaz was approved for birth control with added side benefits of helping premenstrual dysphoric disorder (PDD) and acne, however the ads showed women kicking around balloons that said stuff like “mood swings” and “fatigue” while they played the songs “Good bye to You” or “We’re Not Going to Take It.”

Goodbye to you too, Yaz

Following this they got admonished by the FDA which led to the unusual settlement of being an ad campaign out to UNDO the effects of the advertising. You see, it wasn’t approved to treat PMDD and acne, and in any case not all women have PMDD or untreated acne, even though the makers of Yaz certainly wish that that was the case. They were promoting it as a lifestyle drug, like look good, get laid, and feel good about yourself. What more could women want? Anyhoo in the new ads an actress looks into the camera and says:

You may have seen some Yaz commercials recently that were not clear. The F.D.A. wants us to correct a few points in those ads.

Indeed. Well first of all I really hate it when they take a perfectly good song and associate with some cheesy product. They should make musicians sign a contract that they will never sell out their tunes which run around in our heads. Second, that $20 million is “chump change” as one commenter pointed out, after they have already made their billions promoting a product for something that it wasn’t approved for, something that can be thought of as the cost of doing business, kind of like the billion that Eli Lilly paying as punishment for off label promotion of Zyprexa not being a big deal when they made 20 billion out of the deal. Finally, noone pointed out the fact that Yaz (and is sister pill Yasmin) (as I have written about before in “Is Your Birth Control Pill Driving You Bananas“) is the mosted posted about medication on medications.com, with most of the women complaining about how it makes them MORE depressed and anxious. Yaz also has drospirenone, a type of progesterone that can lead to elevations of potassium and potential heart failure.

How can it be that your birth control pill makes you depressed? Birth control pills (or oral contraceptive pills, or OCPs) are combinations of sex hormones related to estrogen and progesterone. Normally these sex hormones cycle throughout the month. In addition to controlling reproduction they also have effects on the brain, which is why they can cause anxiety and depression.

Taking the pill effectively blunts the normal variation in hormones; it also eliminates ovulation, which also affects sexuality. In fact, one study showed that strippers who were ovulating made $15 more per hour than strippers who were not ovulating,
and that strippers on the pill made significantly less than other strippers.

You can read more about the relative risks of heart disease and cancer in women of different ages and smoking status in my last post on this topic. However, I recommend using an IUD as the safest form of birth control, or a progesterone only pill.

A study of 16,690-persons whose results were released today by Medco Health Solutions found that patients taking Plavix (clopidogrel) with a proton pump inhibitor (PPI) like Nexium or Prilosec have a 50% increase in risk of major cardiovascular event and 74% increase in heart attacks compared to people taking Plavix alone. Since Plavix is given to prevent heart attacks as an expensive alternative to aspirin, it seems these people are losing their benefit.

Where does that leave us? Well since about half of plavix users are on Nexium or another PPI to prevent stomach bleeding, we have to ask what is the benefit of Plavix for these people? So what has the data been for Plavix in the prevention of cardiovascular events been up to now.

In the CAPRIE study Plavix treated patients showed an 5.32% annual rate of a composite measure of stroke, heart attack, or vascular death, compared with 5.83% on aspirin treated patients, a difference that was barely statistically significant (CAPRIE 1996). In the CHARISMA trial of patients with heart disease or risk factors for heart disease there was no significant difference between those who were given clopidogrel plus aspirin or aspirin alone in the combined incidence of heart attack, stroke, or death from cardiovascular causes (Bhatt, Fox et al. 2006). In the CLOpidogrel and Metoprolol Infarction Trial (COMMIT) 45852 patients with a heart attack within the past 24 hours were given clopidogrel or placebo in addition to aspirin. Clopidogrel patients had a 9% reduction in a combined measure of death, heart attack or stroke, a difference that was statistically significant (COMMIT 2006). An analysis of all of the published studies showed a 10% reduction in heart attacks and strokes in patients with a history of cardiovascular disease when clopidogrel was added to aspirin (ATC 2002). These differences, however, translate into a less than 1% reduction in absolute risk. In the Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH)(Diener, Bogousslavsky et al. 2004) study 7599 patients with recent stroke or TIA with one other risk factor for heart disease were randomly assigned to receive clopidogrel or clopidogrel plus aspirin. There was no difference in rates of combined stroke, heart attack, or hospitalization between clopidogrel (17%) and clopidogrel plus aspirin (16%); a 1.3% increase in bleeding was not statistically significant. In a study of 320 patients who had developed a bleeding ulcer while taking aspirin to prevent heart disease, after the patients’ ulcers healed they were randomized for a year to re-treatment with aspirin or clopidogrel. All of them also received esomeprazole. The patients who took clopidogrel had more gastrointestinal bleeding (8.6%) than aspirin patients (0.7%), a difference that is striking (Chan, Ching et al. 2005).

It looks like with these new study results it looks like whatever meagre advantage Plavix has over aspirin are more than offset in people on Nexium as well. It is hard to see what role Plavix has now in heart attack prevention relative to the cheaper aspirin.

ATC (2002). “Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.” British Medical Journal 324: 71-86.

Bhatt, D., K. A. a. Fox, et al. (2006). “Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.” New England Journal of Medicine 354: 1706-1717.

CAPRIE (1996). “A randomised, blinded trial of Clopidogrel versus Aspirin in Patients At Risk of Ischaemic Events (CAPRIE).” The Lancet 348(9038): 1329-1339.

Chan, F. K. L., J. Y. L. Ching, et al. (2005). “Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding.” New England Journal of Medicine 352(3): 238-244.

COMMIT (2006). “Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.” The Lancet 366: 1607-1621.

Diener, H.-C., J. Bogousslavsky, et al. (2004). “Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial.” The Lancet 364: 331-337.

COMMENTS

Dan Abshear commented on November 12, 2008

Notable is that Plavix is the number 2 best selling drug, and Nexium is the number 3 best selling drug. Both have held this position for years. Perhaps they have been promoted to be prescribed together in this manner as well, one may speculate.

As to the etiology with increased CV events when both are used together, that has not been explained, I understand.

Yet as Nexium molecularly is identical to Prilosec, which is now OTC, Plavix can and has been considered simply an expensive aspirin with no significant benefits when comparing these two drugs. It appears there needs to be a warning letter to doctors regarding this danger, along with clarification on efficacy issues as well.

Doug Bremner commented on November 12, 2008

I think the speculation is that Nexium affects an enzyme involved in Plavix metabolism. I think many physicians do prescribe Nexium to avoid bleeding problems with Plavix or aspirin. Yes this does seem to be another boondoggle with many people taking a drug combo that could have made their problems worse.

[Originally posted November 12, 2008]