Who Needs Those Cholesterol Pills, Anyway?
41 CommentsBy Ed Silverman // January 18th, 2008 // 4:00 pm
That’s the question pondered in a BusinessWeek piece, and the answer offered - very few. To illustrate the point, the fine print in a Lipitor ad is cited - in a large clinical study lasting more than three years, 3 percent of patients taking a placebo had a heart attack, compared with 2 percent on the Pfizer pill. This means for every 100 people, three people on placebos and two people on Lipitor had heart attacks.
The difference credited to the drug? One fewer heart attack per 100 people. So to spare one person a heart attack, 100 people had to take Lipitor for more than three years. The other 99 got no measurable benefit. In other words, the number needed to treat (or NNT) for one person to benefit is 100. And the mag notes there are reasons to believe the overall benefit for many patients is even less than what the NNT score of 100 suggests, because it was determined in an industry-sponsored trial using carefully selected patients with multiple risk factors, which include high blood pressure or smoking.
“Anything over an NNT of 50 is worse than a lottery,” Nortin Hadler, professor of medicine at the University of North Carolina at Chapel Hill and a longtime drug industry critic, tells the mag. “There may be no winners.” Drugmakers, however, advertise big percentage drops in, say, heart attacks, while obscuring the NNT. But when it comes to side effects, they flip-flop the message, dismissing concerns by saying only 1 in 100 people suffers a side effect, even if that represents a 50 percent increase. (Click on the BusinessWeek chart for a clearer view).
Several recent scientific papers, meanwhile, peg the NNT for statins at 250 and up for lower-risk patients, even if they take it for five years or more. “What if you put 250 people in a room and told them they would each pay $1,000 a year for a drug they would have to take every day, that many would get diarrhea and muscle pain, and that 249 would have no benefit? And that they could do just as well by exercising?” asks Jerome Hoffman, professor of clinical medicine at the University of California at Los Angeles. “How many would take that?”
Probably not too many. But for those willing to gamble, John Mack at PharmaMarketing, who drew this to our attention, is collecting your money.
Nathan
Ok, where should I start… This is why journalists should have a background in science, or at least have some good scientific advisors.
The NNT is so high because the risk of dying of a heart attack is so low. The overall reduction (3% to 2%) is a 50% reduction. That’s very significant, and if the entire 50 million US adults over the age of 65 were taking this medication, it would translate to 500,000 fewer heart attacks per year. Granted, not every adult over the age of 65 has high cholesterol, but many do.
Here’s a question: How many people in the US die of AIDS every year? Far less than die heart attacks, that’s for sure. If someone came out with an effective AIDS vaccine tomorrow, you can bet there would be a national immunization drive almost immediately. What would the NNT be on an AIDS vaccine? Far higher than 100. What about the cervical cancer vaccine (Gardasil)? It’s purely a guess, but I would say far less than 3 in 100 women get cervical cancer in any given 3 year period. Thus, the NNT would again be far higher than 100.
The NNT is a great way to look at things when you are talking about a flu or cold treatment. Then you have a point. But when the risk factor is something LIFE THREATENING (like a heart attack, AIDS, or cancer), then the acceptable NNT can AND SHOULD be far higher.
Jack2
I tried to think of the most unquestioned safety intervention and came up with seat-belts. Would you question seat-belt use? What is the NNT for seat-belts?
My yahoo search turned up:
Seatbelts saved 15,434 people and airbags an additional 2,647 lives during the same period (2005).
Based on Nathan’s estimate Statins prevent 500,000 heart attacks per year. If society had to choose between seat-belts or statins, we would save more lives with statins (granted seat-belts carry fewer side-effects and probably cost less).
I’m a pharmacist (disclaimer: and an employee of the pharmaceutical industry-but I don’t work on statins in any way shape or form, or for a company that makes a statin), and I told my dad to get on a statin. I consider them the greatest recent advance by the pharmaceutical industry. Unless something better comes out between now and then, I will go on them if/when I develop hypercholesterolemia. Let’s not encourage people to stop taking a life-saving med.
safetycenter.navy.mil/…/Seatbelts_Save_Sailor_and_Marine_Lives.doc
Bob Freeman
Nathan and Jack2, enjoyed reading your insights on an important AND neglected topic.
My cynical view is that as long as Americans consider death to be optional we will continue to see statins and drugs like clopidogrel being used without a lot of questions being asked.
Doc
I am a 20 year vetran of big pharma field sales and marketing. The spin that big pharma uses as pointed out in this article is standard operating procedure. We ALWAYS spin benefits bigger than reality and diminsh side effects and other issues smaller than reality. This is news?
Nathan
Bob,
That’s a good point. Historically, the pharmaceutical industry (and the medical profession in general) has been in the business of saving lives and making dramatic improvements in public health. As many major diseases now have effective treatments, we are forced to shift our mission to simply “delaying death” and making incremental improvements in health. How much money will society be willing to spend in order to increase the average life expectancy by another 5 years? Is it worth the cost?
That’s certainly not a question you see addressed by anyone with a financial interest in the healthcare industry (except maybe the insurance companies). As long as we have a “free market†healthcare system, consumers can make that decision for themselves as treatment costs go up and up and up. However, as those costs go up, many people are pushing for a more socialized health care system. The true cost of those incremental gains are masked – so now it’s left up to the politicians and world leaders to answer the tough question I posed above: How much money will society be willing to spend in order to increase the average life expectancy by another 5 years? Is it worth the cost?
I don’t have a very bright view of the future of our industry when I think about things from a broad perspective like that….
CVMD
Statins are great drugs - some better than others. They have been shown to work over and over again. They are particulalry valuable in patients who have already had an event or have existing disease. Primary prevention is not as yielding, but very high risk patients should definitely be considered for treatment.
It’s unfortunate that this whole fiasco with ENHANCE has muddoed the waters. Schering-Plough and Merck have done major harm to the public health by being so irresponsible in the first place. There’s a lot of difference between an impact on atherosclerosis and reducing events. reducing events is key.
Dr. Remulac
The NNT discussion is incomplete without including the economic side of the picture. For the statin secondary prevention trials, the NNT presented is ~20, which is commonly accepted as being hands-down good. But, is it really?? You absolutely have to consider the duration of the trials from which that NNT was derived in order to fully interpret it and to correctly apply it. In this case, that is 5 years. So, what this really means is that you have to treat 20 patients for 5 years in order to prevent a single major CV event. Now, the average major CV event costs somewhere in the $25,000 to $30,000 range. Take the best-case scenario of generic statins which now cost about $1/day. You have to spend $1/day x 365 days/yr x 5 years x 20 patients or $36,500.00. That’s MORE than the cost of the event itself, and not as great a health economic value as everyone thinks. Take the case of branded statins that cost anywhere from $3-$5/day. At $3/day you have to spend $109,500.00 and at $5/day it’s $182,500.00 and no health economist will tell you that is a good value for society. Don’t get me wrong, statins do reduce the risk of events in several important patient groups (post-MI, diabetes, post-ACS, etc), but their value is much less than people realize. Food for thought….
Atlex
Dr. Rumalac, your thought process places no value on NOT having an event. So what if it costs more to prevent an event than it does to treat an event. Does the pain, suffering, and death associated with an event have no value? Of course, for anyone with a job, there’s also the lost wages , as well. I gladly take a statin, knowing the cost, because I prefer avoiding an event that is painful, does cause suffering, and could kill me at a younger age. I hope you aren’t a practicing physician; I would never want my physician to place no value on a patient’s plight. There is another flaw in your thnking. Takoing the approach you do assumes that a branded statin maintains its high cost forever. In reality, anyone starting on say Lipitor, generally recognized as the premier statin, today would only be paying brand costs for two or three years and then get the cost advantage of generic products for years to come. By the way, for most large health plan customers, the $3 to $5 a day is not the actually cost after rebates and discounts; the cost is substantially lower. Patients, of course, pay only co-pays, which run, in many case ~$1 a day.
Jack2
Just to expand on Dr. Remulacs great post…
The old rule of thumb was about $50,000 for one QALY* (Quality Adjusted Life Year). So if a drug costs $50k dollars and adds one perfect year of health then it’s worth it.
If alternative drugs are available, and a drug costs $50k more than the next best drug, it needs to add one more QALY then that next best drug.
I don’t think the goal post has moved for a while, so a lot of economic studies I see now run it at a $50k/QALY threshold and what’s probably a more reasonable $100k/QALY threshold.
I remember reading a while ago (and could not find a source from it now) that it costs $100,000 per life saved by seat belts. So we, GM and Toyota and others, as well as automobile consumers pay an extra $100k to have seat belts installed in cars. This is considered to be pretty much the best deal in safety. On the other hand, when the government bans a cancerous compound from paint or something, it costs society much more than $100k/life saved.
What also makes seat belts so great is they save everyone from 8-80. If a drug only saves people who are already 80, then how much life span does it really add? When you save an 8 year old from dying with a seat belt you just added about 70 QALYs.
*QALY: If a person got a treatment that added 365 great days to their life than that would add one QALY. If a drug added 2 years to a persons life, but half of those days were no good (maybe an Alzheimer Disease drug that only left someone cognitively aware about every other day) it would also add 1 QALY. If it added one year, and half those days were bad, it would add 0.5 QALYs.
Lisa Van S
And the cost of Rhabdomyollysis?…Which is a well known side effect, and patients quite often ignore their symptoms believing it will go away. Better education on this side effect is needed.
Atlex
Lisa,
Rhabdo is a very rare side effect in both clinical studies and in real life. Of course, it should be built into the equation.
Atlex
Lisa Van S
I had experienced it with a family member, it may be rare but its still pretty scary. I just like to be informed.
Dr. Remulac
Atlex - you are completely missing the point of my statements. You are exhibiting a classic flaw in lay/medical thinking called the “fallacy of ecological analysis”, but don’t feel bad - so does NCEP and many other so-called expert bodies. My argument is from the SOCIETAL perspective, not the individual patient perspective. The fallacy of ecological analysis occurs when you make judgements about an individual based on population data when the patient may actually have nothing in common with the population from which the data you are applying were drawn. JACK2 raises some nice points about adjusting outcomes by applying QALY’s. It is true that the economic argument muist be integrated with impact on the individual patient. There are many arguments regarding the upside and downside of QALY’s, but in the end (as ATLEX also points out), the wishes/wants/needs of the individual patient must be considered on the patient-level. However, at the patient-level, all the population data are surprisingly meaningless. In this world, we have to make smart decisions about how we allocate heathcare dollars, and that must be done from a societal perspective and that is what I was discussing. Cholesterol-altering drugs account for about $24 BILLION dollars of our healthcare spending. We’d be foolish as a society to not have some reasoned understanding of the value we get in return for those $$$ spent.
Dr. Remulac
ATLEX - on the point of factoring-in the health or economic impact of rhabdomyolysis - it has zero impact on a population/societal basis because it is such a rare event (less than one case per every million prescriptions filled). Clearly, it means a lot to the individual patient that experiences it.
Bob Freeman
Dr. Remulac and Jack2, again, great posts.
I worked in the health economics field for about 20 years and, frankly, lost interest in its application. The scenarios both of you presented were sound; however, when one examines assumptions and includes sensitivity analyses on issues such as compliance and duration of therapy, one gets diverse variations in QALYs and any other outcome measure. To be blunt, I find QALYs of academic interest only and virtually useless in decision-making.
It is the bottom line; i. e., the net financial impact on the drug budget that matters to payers (excluding the UK and Australia and Canadian provential formularies).
a drug developer
Great discussion and you are helping me with a presentation I have to make. Is my logic below on your arguements correct?
Cardiovascular disease death rates dropped 23.1% between 1993 and 2003 during a time when leading indicators like obesity and inactivity were moving in the wrong direction.
Of course correlation is not the same as cause but..
The NNT is so high because the risk of dying of a heart attack is so low. The overall reduction (3% to 2%) is a 50% reduction.
Incidence — 1,200,000 new and recurrent coronary attacks per year. (National Heart, Lung, and Blood Institute’s Atherosclerotic Risk in Communities [ARIC] Study and Cardiovascular Health Study (CHS). About 38 percent of people who experience a coronary attack in a given year die from it..
So if all of these people took a statin there would be 600,000 fewer heart attacks per each of the five years or 3 million fewer heart attacks.
economic effects of statins
You need to consider the duration of the trials from which that NNT was derived in order to fully interpret it and to correctly apply it. In this case, that is 5 years. So, what this really means is that you have to treat 20 patients for 5 years in order to prevent a single major CV event. Now, the average major CV event costs about $30,000 .but remember that about 38 percent of people who experience a coronary attack in a given year die from it while the statin prevented 50% of the patients from having a heart attack in the first place. Generic statins which now cost about $1/day. You have to spend $1/day x 365 days/yr x 5 years x 20 patients or $36,500.00. That’s MORE than the cost of the event itself. But not by too much. And what would you rather suffer, a pill a day or a CV which carries a 38% chance of death? You will not die from taking a statin.
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Atlex
Dr. Remulac, the point I was making about rhabdo was exactly that; it is rare. I was humoring Lisa by including it in the final equation. In the end, the impact on the QALY calculation is as you suggest close to zero. Ultimately, I agree with the drug developer with regards to the offset of taking a pill vs. a CV event.
Lisa Van S
Atlex
What is so humerous about a patient suffering from Rhabdo!. Its also important to note that only 10% of side effects are ever reported to FDA. Hopefully the 800 medwatch # that will be placed in all DTC adds will change that.
Atlex
Lisa,
I was using the term in a different way. You brought up rhabdo and, despite the fact that I knew that including it in any value equation would make little to no difference in the outcome, I agreed with you that it should be accounted for.
Atlex
Bob Freeman
Do consider, though, in developing decision trees or markov models that the low rate of compliance and duration of therapy will reduce the effectiveness of the drugs considerably, thereby reducing any cost effectiveness ratios that one might construct. If I recall, correctly only about 30% of those who start statin therapy are still taking the medication after 1 year. To assume full compliance is not warranted.
Bob Freeman
By the way, to do one of these long-term cost effectiveness models one should consider that increased life span is also associated with the incidence of other diseases: cancer, congestive heart failure, etc. So, you prevent premature death from one cause only to allow time for other serious conditions to occur. No one ever does these calculations or rarely if ever.
DAB
Ed,
Great analysis. The fact that the Pharmas folks (I’m one for 20 years, and I take Lipitor) can’t get comfortable with the real value of the drugs they sell demonstrates the reason that this Industry is ranked below Geo. Bush, car dealers, and lawyers in public perception. The fact that no one is paying attention to the man behind the curtain doesn’t mean there really is a wizard. Marketing spin onlt looks good to those who WANT it to look good. When we try to spread data too thin to make it look better than it is makes us all look bad. The analysis as you have stated it makes the average person willing to pay for their medication and feel ggod about that value- just not the Federal Govt who pays for 50% of all drugs.
Lisa Van S
Atlex,
Thank You,..Cant ask for anything more.
Drug Developer
Bob;
Re: your comments on compliance
You bring in another good point but I think that it might be off topic. Are you not talking about the difference between efficacy and effectiveness? The Economist had a great article on that recently. You can see it here.
http://www.economist.com/finance/displaystory.cfm?story_id=10498550
I copies out a section of it below
…. One is the difference between efficacy and effectiveness. Most studies of drug efficacy look at how the pills perform under ideal conditions with hand-picked patients. In the real world, though, the effectiveness of a new pill will vary greatly depending on whether patients take the pills correctly, what other medication they are on, and so forth. Running randomised controlled trials, which adjust for such variables, would help to address these concerns but are far more expensive.
Another set of problems lies in the interplay between comparative-effectiveness analysis and health-care innovation. Drugs firms are innovating at a fearsome pace. If governments demand that all new drugs and devices undergo rigorous studies to prove their effectiveness, the rate of medical breakthroughs could slow. Bio, a lobbying group representing the biotechnology industry, argues that comparative studies would risk penalising future patients in favour of today’s by dampening the pace of innovation.
If studies are too time-consuming, they may also be rendered irrelevant by fast-moving markets. One comparative trial in the early 1990s laboriously compared balloon angioplasty and bypass surgery over the course of many years; but the widespread adoption of innovative heart stents in the meantime made the results of the study almost meaningless……
So, my point is, do you throw the baby out with the bathwater because compliance is low? I take Lipitor and am compliant for over a year. I am glad to have the choice of the drug. Regarding the individual vs society does the low compliance rate change the math? Those people who drop their meds are than increasing society’s # of CV events and incurring the number of $30,000 charges.
Drug Developer
To DAB;
I don’t feel like we are trying to thinly spread data. This is a complicated story with involved analysis. I would put more of the blame on our inability to communicate properly the cost/benefit analysis.
Ultimately, it does come down to how we want to spend our resources both as individuals and government’s money (which we can influence to some degree).
Everyone will agree that health is more important than money. Maybe we would like to have a lower morbidity up until we die. Maybe we should spend more time figuring our comorbidity rates.
Bob Freeman
Drug Developer, yes, I was differentiating effectiveness from efficacy. My point in bringing this up is that key drivers’ assumptions need to be subjected to sensitivity analyses.
One other point, the most powerful CEAs are found in subpopulations, viz., patients at risk. The ratios are much more favorable than those derived in general populations.
Finally, it is a misunderstanding of the term cost effectiveness–to say a therapy is cost-effective on whatever criterion one might have selected, does not mean that it saves money. Most drug thereapies add to pharma expenditures, even breakthrough therapies.
a drug developer
Bob (and others)
If we restrict the admin of statins to patients at risk, so using the NNT of 20:1. Prescriptions wider than that seems plainly wrong from the analysis below.
Incidence — 1,200,000 new and recurrent coronary attacks per year. (National Heart, Lung, and Blood Institute’s Atherosclerotic Risk in Communities [ARIC] Study and Cardiovascular Health Study (CHS).
So if all of these people took a statin there would be 600,000 fewer heart attacks per each of the five years or 3 million fewer heart attacks. $3 million heart attacks times $30,000 each = $ 90 billion in costs just from CV
The drug treatment over those five years ‘only’ 1.2 million * 5 years*20 NNT*365 days= $43 billion
Drugs are cost effective compared to the alternative.
Nathan
A Drug Developer:
I like the conclusion that you came to, but there is a problem with you logic: All those 1.2 million CV events are not due to high cholesterol. The 50% reduction is likely to only be observed in whatever percentage of that population have high cholesterol.
This is a great discussion — it’s a complicated issue. Not nearly as simple as the BuisnessWeek (or Ed’s) article makes it seem.
Lisa Van S
Nathan,
Gee,.. isnt it great that Ed has a place where one can have a great discussion on complicated issues!!…
Hank
Agreeing that this is an excellent discussion that I will use in a course (unless Ed and the rest of you demand royalties). So you should all know you will be influencing a lot of young minds, many pre-med, pre-pharm, etc..
It’s nice to get to the heart of things (so to speak).
Bob Freeman
Drug Developer et al., I wasn’t arguing for restricting prescribing to groups at high risk, only pointing out that sub-group CEAs tend to have higher CEA outcomes.
Nathan’s point on high cholesterol being the only determinant of either fatal or non-fatal events is very appropriate. The effects of other causes and confounding variables has to be recognized.
a drug developer
ok let me refine my math a little than on the c/b. Instead of saying that statins save 600,000 lives per year how about that there is still a 50% reduction in heart attacks of a group X (x being a group who have risk of heart attack every year from high cholesterol)
untreated and having heart attacks that costs x/2 * 5 years * $30,000/cv = $75,000x
The drugs cost x * 20 * 5 years * 365 = $36,500x
still half the price of not treating. I appreciate your evaluating this as I want to make an accurate presentation.
Joseph
How about taking something 100% natural to lower cholesterol and promote overall good health???
I believe Kevin Trudeau!!!
NATURE is where health is found:)
NOT YOUR FUKKING PILLS!!!!
Bob Freeman
Drug developer, the calculation looks good to me, but there’s no reason for you to not include the original case (the base case, if you will)also and then present the new case as a sensitivity analysis. there are other scenarios that could be created but you don’t have to go any farther.
Nice job, by the way.
One of the problems presenting CEAs is that people will nit pick you to death over numbers. Just state your assumptions and be transparent.
DR. Remulac
Clearly, no one is saying that patients who are at high risk of a heart attack and have elevated LDL-C shouldn’t be treated with an appropriate LDL-C lowering drug. That’s not the issue. The issue is this: NCEP, ADA, AHA, and other major medical societies have declared that high-risk patients have a a goal LDL-C of
MKM
3% to 2% is a 33% risk reduction, not a 50% risk reduction.
a drug developer
yes Nathan I have been stewing over that 50% vs 33% reduction since you (and I) wrote it. I think that MKM is right but the conclusion is still the same that the drugs are cheaper $49,500 vs $36,500.
and if you go to the clinical data at
https://www.pfizerpro.com/product_info/lipitor_pi_clinical_studies.jsp
some studies are even better. ie stoke reduction of 48%. as several people have mentioned there are several reasons to prescribe beyond just CV.
a drug developer
and the cv reduction is 36% in the data.
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