10312014Headline:

Cherry Hill, New Jersey

HomeNew JerseyCherry Hill

Email Mike Ferrara Mike Ferrara on Avvo
Mike Ferrara
Mike Ferrara
Attorney • (866) 735-1102 Ext 650

Vioxx Killed Half a Million? The Facts Are Grim.

6 comments

It’s looking more and more likely that the Merck painkiller Vioxx, the blockbuster drug suspected of having caused more than 55,000 deaths from stroke and heart attack before being withdrawn from the market in 2004, actually killed many more people than we previously thought.

While conducting research on America’s media coverage of the Vioxx scandal, publisher of The American Conservative Ron Unz noticed some figures that seem to have escaped almost everyone else’s attention. The year Vioxx was introduced, 1999, showed the largest recent rise in American death rates. The year after Vioxx was pulled from the market, American death rates underwent a substantial and completely unexpected decline.

"We find the largest rise in American mortality rates occurred in 1999, the year Vioxx was introduced, while the largest drop occurred in 2004, the year it was withdrawn," says Unz. "Vioxx was almost entirely marketed to the elderly, and these substantial changes in the national death-rate were completely concentrated within the 65-plus population.

"The FDA studies had proven that use of Vioxx led to deaths from cardiovascular diseases such as heart attacks and strokes, and these were exactly the factors driving the changes in national mortality rates."…

This drop corresponds to roughly 100,000 fewer deaths per year. The age-adjusted decline in death rates was considerably greater. –The Week

The numbers suggest that Vioxx may have caused more than 500,000 premature deaths. This is so far beyond the 3,468 that were named in Merck’s class action settlement for $4.85 billion in 2007 that it boggles the mind. Further investigation is clearly needed to determine just what effect Vioxx had on the almost uniquely elderly population that took it. And Merck needs to be held accountable for the colossal harms it has caused.

6 Comments

Have an opinion about this post? Please consider leaving a comment or subscribing to the feed to have future articles delivered to your feed reader.

  1. Peter Schaeffer says:
    up arrow

    The TAC needs to do some fact checking before publishing something like this. If Vioxx actually resulted in 500,000 premature deaths it would have shown up in the overall death rate. It didn’t. See “National Vital Statistics Reports” (http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf). The overall and age-adjusted death rates fell from 1999 to 2005. Indeed, the age-adjusted death rate fell faster after 1999 than it did before.

    If the 500,000 statistic was correct, there should have been at least 100,000 incremental deaths in the peak year from Vioxx. That’s 33 per 100,000 for the entire U.S. See any blips in the data of the magnitude? They don’t stand out…

    Of course, the incremental deaths should really show up in the CVD (cardiovascular disease) mortality statistics. They don’t. See “US Death Rates 1975-2009″ (http://seer.cancer.gov/csr/1975_2009_pops09/results_merged/topic_graph_heartdis_cancer.pdf). Also see some Arizona specific data (“Trends in Age-Adjusted Mortality Rates of Deaths due to Cardiovascular Disease, Arizona and US, 1980-2004″ – http://www.azdhs.gov/azcvd/documents/pdf/az-burden-of-cardiovascular-disease.pdf). The Arizona data is not by itself particularly important (state level death rate variations are huge). However, the Arizona data exactly tracks the U.S. overall data.

    Is it possible that Vioxx resulted in 50,000 deaths over the period in question? Sure. I don’t have anything approaching the background to evaluate such a claim. I wouldn’t be surprised either way as to the truth. For the record, I do have opinions on topics like this. I spent years deflating Thiomersal / autism claims…

    However, there is a larger issue here. NSAIDs (Celebrex, Vioxx, Bextra, etc.) are all associated with incremental mortality. Indeed, even Naproxen (also a COX-2 NSAID) has been linked to higher death rates. However, these drugs are simply too valuable to give up. Ask the people who take them, if anyone has any doubts. For many, NSAIDs are the difference between a normal life and ongoing, severe pain.

    This is why the FDA panel voted 31-1 to keep Celebrex on the market. The same panel also voted 17-15 to keep Vioxx for sale. Even excluding panelists with industry ties, the vote was 8-14 (losing) to approve Vioxx. If Vioxx was really as bad as some allege, why did 8 panelists (with no industry ties) favor its continued sale? Why was the vote in favor of Celebrex (which is also linked to CVD) almost unanimous? See “10 on FDA Vioxx panel had ties to companies ” (http://www.msnbc.msn.com/id/7031927/ns/health-arthritis/t/fda-vioxx-panel-had-ties-companies/#.T6lukFJpe18)

    Thank you

    Peter Schaeffer

    P.S. I have no ties to the drug industry (other than as a customer). I was once prescribed Naproxen many years ago. It was astonishingly helpful even though I only took it for a week or two. I have taken Aleve (OTC Naproxen) from time to time.

  2. Peter Schaeffer says:
    up arrow

    A few more notes.

    1. If Vioxx had anything approaching the impact TAC (The American Conservative) is suggesting, it would have shown up in the CVD death statistics first and foremost. It doesn’t.

    2. Vioxx was withdrawn on September 30th, 2004. Many folks probably continued to take their pills for a few weeks longer. If Vioxx was really so deadly that removing it from the market for the last 3 months of 2004 had a material effect, then much larger increased in death rates should have shown up sooner. Indeed, since it was still on the market for most of 2004, the largest impact on death rates should have been from 2004 to 2005. In fact, the crude death rate rose from 2004 to 2005. Evidently, removing Vioxx raised death rates.

    3. The age-adjusted death rates tell a more useful story. The age-adjusted (AA) death rate plunged from 2003 (832.7) to 2004 (800.8). From 2004 (800.8) to 2005 (798.5) it was almost flat. Removing Vioxx from the market stopped (for a while) progress in reducing death rates.

    4. The introduction of Vioxx provides even stronger evidence. Vioxx was introduced on May 20th of 1999. However, sales were slow at first. Only 4.845 million prescriptions were written in 1999. The number of prescriptions rose to 20.630 million in 2000 and 25.406 million in 2001 (the peak year). The crude death rate rose from 847.3 in 1998 to 857.0 in 1999. However, it fell to 854.0 in 2000, and 848.5. Evidently an extra 15 million Vioxx prescriptions in 2000 reduced the death rate as did another 5 million in 2001.

    5. The AA death rates tell an even better story. The AA death rate rose from 870.6 in 1998 to 875.6 in 1999. However, the extra 15 million Vioxx prescriptions reduced it to 869.0 in 2000 and another 5 million Vioxx prescriptions reduced it to 854.5 in 2001. As mentioned above, the AA death rate falls from 832.7 in 2003 to 800.8 in 2004 (with Vioxx still on the market for most of the year). It then essentially flat lines in 2005 (798.8).

    6. The use of crude death rates is ultimately misleading. The American population is obviously aging. AA death rates make considerably more sense. In a few years, the baby boomers will start dying off in large numbers. The crude death might even rise. What does that demonstrate other than the pig coming out the other end of the Python?

    7. Obvioiusly everyone will die eventually and that 500,000 is an estimate of premature deaths. Premature by how much? A year? A month? One second? If the reduction is material it should show up in death rates (AA and crude). It doesn’t.

    8. Death rates rise and fall for reasons clearly unrelated to Vioxx. The crude death rate rose from 1994 (866.1) to 1995 (868.3) and from 816.5 in 2004 to 825.9 in 2005.

    9. See Table 8 http://www.cdc.gov/nchs/data/nvsr/nvsr49/nvsr49_08.pdf for a comparison of 1998 versus 1999 death rates. The overall death rate fell in the 65-74 cohort while rising 75-84 cohort and the 85+ cohort. CVD fell in both the 65-74 cohort and the 75-84 cohort from 1998 to 1999. The CVD death rate rose for the 85+ cohort from 1998 to 1999.

    See also Table 9 in http://www.cdc.gov/nchs/data/nvsr/nvsr50/nvsr50_15.pdf for a 1999 to 2000 comparison. As Vioxx prescriptions soared (quadrupling to 20 million) all 65+ death rates fell. The CVD 65+ death rate also fell.

    10. In the last pre-Vioxx year the overall death rate was 847.3. In 2003 with Vioxx going strong, it was 841.9. In 2004 (14 million Vioxx prescriptions) it was 816.5. Of course, the age-adjusted data show that Vioxx “saved” even more lives. The 1998 AA rate was 870.6. The 2003 rate 832.7. The 2004 rate was 800.8.

    11. The crude death rate was essentially flat from 2004 to 2005 when it should have fallen the most. The 65+ data is more dramatic. Table 9 of http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_10.pdf shows 65+ mortality rates fell every year from 1999 to 2008. So did the CVD death rates.

    12. Any alleged linkage between Vioxx going off the market in 2004 and mortality statistics suffer from a basic flaw. Vioxx was recalled on September 30. September 30th isn’t Jan 1.

    Thank you

    Peter Schaeffer

    P.S. I am not claiming that Vioxx was harmless. NSAIDs are (apparently) intrinsically dangerous. However, the incremental deaths were too few to show up in the overall mortality statistics and more decisively, too few to show up in the CVD mortality statistics.

  3. Peter Schaeffer says:
    up arrow

    A few more notes

    1. There were rumors that Vioxx was dangerous before the recall. Indeed the claims predate FDA approval (clearly another story). However, rumors aren’t numbers. There were 19.959 million Vioxx prescriptions in 2003 versus 13.994 million in 2004. That’s a fall of 5.965 million. However, the fall from 2004 to 2005 was 13.994 million. Yet, somehow raw (but not AA) death rates fell from 2003 to 2004 and rose from 2004 to 2005. 2004 Vioxx prescriptions were 70.11% of 2003. That’s only slightly below the 75% we would expect from the withdrawal date. In other words, physician avoidance (pre-recall) was quite modest at best.

    2. Total COX-2 sales did not plummet in 2004. The IMS data shows that they were flat or down slightly. Let me quote from “IMS Health, National Sales PerspectivesTM, 2/2005″

    “Despite the negative publicity and the voluntary withdrawal of Vioxx®, the COX-2 inhibitor class was flat for 2004 with sales of over $5.3 billion. Celebrex® remained the largest product with sales of $2.7 billion and Vioxx® achieved sales of $1.8 billion in the first nine months of the year before being withdrawn on September 29.” The link is http://www.imshealth.com/portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=003a1d3be7a29110VgnVCM10000071812ca2RCRD&vgnextfmt=default

    Other sources show Celebrex and Bexta sales peaking in 2004. Another report from IMS makes this point and suggests a decline in total COX-2 sales. See “Biotech Remains Industry Growth Engine, With 17 Percent Sales Growth”. The key quotes are

    “Merck’s surprise, voluntary withdrawal of Vioxx® in September and potential safety concerns associated with other pain relief medications resulted in doctors switching patients away from Vioxx or starting them on other COX-2 products. Patient volume for the remaining COX-2s initially increased by more than 25 percent following the withdrawal, driven by a 15 percent increase in new therapy starts and a two-thirds share of all Vioxx switches.
    “Over time, COX-2 usage has declined to below pre-Vioxx withdrawal levels, due in part to further safety concerns about this class of drugs,” said Lisa Morris, global director, IMS longitudinal services. “By year-end, the prescription COX-2 and NSAID market saw a 9 percent decline in total patients.” The link is http://www.imshealth.com/portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=933a1d3be7a29110VgnVCM10000071812ca2RCRD&vgnextchannel=41a67900b55a5110VgnVCM10000071812ca2RCRD&vgnextfmt=default. The 9% decline may have been versus the third quarter of 2004 which means that total COX-2 prescriptions could have easily equaled 2003 (which appears to be the case).

    See also “Sales rise for Celebrex and Bextra after Vioxx withdrawal” (http://www.usatoday.com/news/health/2004-11-30-painkillers_x.htm)

    “Pfizer’s Celebrex gained a majority of sales for new-generation painkillers in the month after Merck & Co. yanked Vioxx due to safety concerns, according to IMS Health, a pharmaceutical information company.”

    3. 2005 was a very different story. Vioxx sales were zero of course. Bexta went off the market on April 7th, 2005. Bextra did generate substantial revenues in the first quarter of 2005. However, the retail data (not the entire story) show Bextra growing from 2003 to 2004 (to over $250 million per quarter) and then falling to $148.370 million for all of 2005. Once again this is retail only data. Even though Celebrex stayed on the market with FDA approval, sales crashed in 2005. See “Sales plummet as cox-2 miasma vexes consumers” (http://findarticles.com/p/articles/mi_m3374/is_10_27/ai_n15341417/). Quote

    “According to IMS Health, sales of cox-2 inhibitors have plummeted 65 percent for the first five months of 2005, representing $1.5 billion in lost sales of Bextra, Celebrex and Vioxx. Of those three drugs, only Celebrex remains on the market. And now, two other cox-2 inhibitors that were in the drug development pipeline at the time of the Vioxx withdrawal are not expected to make it to market any time soon–if at all.”

    Another source gives a 48% fall in Celebrex sales in 2005. See “Pfizer to resume airing ads for Celebrex” (http://www.usatoday.com/money/industries/health/drugs/2007-04-01-celebrex-usat_N.htm). Quote

    “The return of Celebrex to TV follows its financial comeback. Celebrex sales hit $3.3 billion in 2004 then dropped 48% in the year after Vioxx’s withdrawal. Last year, Celebrex sales were $2 billion. Still, it ranks behind ibuprofen and naproxen in arthritis prescriptions, according to market tracker Verispan. Before the Vioxx recall, Celebrex was ahead of naproxen but behind ibuprofen.”

    Let’s recap for a moment. COX-2 volumes were flat from 2003 to 2004 and death rates fell. COX-2 volumes crashed in 2005 and death rates rose. This is not the correlation the TAC is suggesting.

  4. Peter Schaeffer says:
    up arrow

    4. Drug companies do give away samples that could impact total consumption in 1999. However, volumes appear to be low compared to prescriptions. In 2007, drug companies spent $8.4 billion giving out samples. See “Pharma scales back drug samples to physician offices” (http://www.ama-assn.org/amednews/2012/03/26/prl20326.htm). Total prescription sales were $286.5 billion (IMS Health).

    The notion that Vioxx early adopters were more at risk is conceivable, but lacking in any substantiation. Why would doctors single out patients with the greatest CVD risk, as the first users of Vioxx? To make such a claim, the TAC needs facts or at least a mechanism (in my opinion). If Vioxx had been the first COX-2 drug on the market this would be a stronger thesis. A person could argue that the sickest patients (in general), with the most pain, were the first users. However, Celebrex was approved on December 31, 1998.

    5. TAC’s use of overall and 65+ death rates suffers from several large problems. The biggest problem is that Vioxx apparently caused heart problems (all of Vioxx’s critics agree on this point). However, there is nothing in the heart disease data to support the TAC thesis. Online data shows that the CVD death rate fell from 1998 to 1999. To be precise the CDC has two sets of data from 1998. The standard data shows a fall for all age groups except for the 85+ group. Overall the rate falls from 268.2 to 265.9. Row 44 (the modified data) shows a slight rise overall (from 264.4 to 265.9) and big falls for the 65-75 group and the 75-84 group. The 85+ group rises as well. Any hint of a spike is absent. The 1999 versus 2000 CVD data show CVD death rates falling for everyone (as Vioxx sales quadrupled).

    Let’s look at this another way. An incremental 100,00 deaths per year is roughly 33 per hundred thousand for the entire population. No shifts of that magnitude show up in the CVD data.

    The NVSS (National Vital Statistics System) data makes the same point. The Major cardiovascular death rate fell from 1998 to 1999 (and kept falling in 2000) for all groups except for the 85+ cohort as Vioxx sales soared. Even the 85+ cohort is below 1998 levels in 2000. There is a big fall from 2003 to 2004. However, that should have occurred in 2005. The data has other big falls as well (1988 to 1989, 1989 to 1990, 2000 to 2001, and 2005 to 2006).

    The subcategories (Heart disease, Heart attack, Chronic ischemic heart disease, Atherosclerotic cardiovascular disease, Heart failure, and Stroke) show the same pattern. Most fall from 1998 to 1999 and 2000. Heart failure and Stroke rise slightly. If Vioxx was nearly deadly as TAC’s assert s , it would show up in the NVSS CVD data. It doesn’t.

    As a check, I graphed CVD mortality from 1998 to 2007. The Vioxx effect is not apparent. The expected spike from 1999 to 2000 and crash from 2004 to 2005 are clearly absent.

    Thank you

    Peter Schaeffer

    P.S. David Graham estimates that Vioxx might have caused 88,000 to 139,000 additional heart attacks / strokes with a 30-40% mortality rate. That’s certainly plausible and not contradicted by the CVD data. Of course, total COX-2 mortality must have been higher because of the side effects of Bextra / Celebrex. As everyone knows, Celebrex remains on the market.

  5. Peter Schaeffer says:
    up arrow

    A few more notes

    1. Vioxx volumes declined by 30% from 2003 to 2004. For the entire year of 2003, Vioxx was dispensed at a rate of 1.663 million prescriptions per month. For the first 9 months of 2004, the rate was 1.555 million prescriptions per month. That’s a decline of 6.5%. Of course, after 2004-09-30 the prescription rate was zero. As the reader can see the decline in Vioxx usage, pre-recall was quite small. Note that Vioxx volumes peaked in 2001 and declined thereafter. Why is not clear. However, Bextra was approved in 2002 and was commercially successful.

    Stated differently, if Vioxx usage fell significantly before the recall it would show up in the prescription numbers. It doesn’t. My data does show a 30% fall from 2003 to 2004. However, that is for the entire year. You can get similar data by checking http://www.modernmedicine.com, This is a “Voice of the Pharmacist” website. The data is retail-only. It very closely matches the statistics I have produced so far (ultimately derived from the same sources, apparently).

    2. Of course, the actual cost of manufacturing brand name pharmaceuticals is a small fraction of the price (much less true for biologics). However, the $8.4 billion cited below is not the “cost” of making the free samples. It’s almost entirely the cost of sending detail agents to doctor offices. If you check the link, you will see that the $8.4 expense included 116 million detail agent visits to doctor offices. At an average cost of $72.41 per visit, obviously the money was spent on wages, salaries, and travel expenses, not manufacturing samples.

  6. Peter Schaeffer says:
    up arrow

    3. It is very unclear if Vioxx caused front-end (the most vulnerable first) or back-end mortality (a cumulative effect). This is an important issue and contrary indications exist. See “Q&A: Vioxx’s Health Risks” (http://www.npr.org/templates/story/story.php?storyId=5415884). Merck tried to claim that there was no adverse impact prior to 18 months. See Figure 2 from “Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial 2005/03/17″ (http://www.nejm.org/doi/full/10.1056/NEJMoa050493). If this claim was/is correct, the entire 1999 / Vioxx thesis is falsified. However, it does not appear to be true (which is why I have avoided it so far).

    Based on additional data and some corrections to the methods used in the original paper, the NEJM published a correction. See “Correction – Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial 2006/07/13″ (http://www.nejm.org/doi/full/10.1056/NEJMx060029). To get a better understanding of the correction, see “Adverse Cardiovascular Effects of Rofecoxib 2006/07/13″ (http://www.nejm.org/doi/full/10.1056/NEJMc066260). The letters from Nissen and Furberg (noted Merck critics) are instructive. They reject the 18 month thesis and suggest an essentially linear cumulative risk model. I quote (from Nissen).

    “The original article included a post hoc hypothesis that curves for confirmed thrombotic events would not begin to diverge until after 18 months of exposure to rofecoxib. However, all intention-to-treat analyses in the newly released report show that the event curves begin to diverge much earlier, generally within four to six months. The most useful Kaplan–Meier curves, involving intention-to-treat analysis of the APTC end point, show divergence after only three months of exposure to rofecoxib”

    At least one author appears to support the 18 month hypothesis (maybe). See “Time-to-Event Analyses for Long-Term Treatments — The APPROVe Trial 2006/07/13″ (http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMp068137&iid=f02).

    Note that none of the NEJM data shows any hint of front-loaded risks. The Merck model claims no incremental risk before 18 months. The contrary analysis seems to show greater risk much sooner. However, the risk is cumulative and linear. The longer a person took Vioxx the more likely they were to have some kind of heart failure as a consequence. Stated differently, they were at greater risk starting soon after they took Vioxx and eventually the risks added up.

    As should be clear, this is deeply problematic for any effort to blame Vioxx for 1999 mortality. Vioxx was dispensed for 7.33 months in 1999 at a rate of 661,000 prescriptions per month. In 2000, the rate was 1.719 million prescriptions per month. It would appear that far more people took Vioxx in 2000, than in 1999. However, a preson could try to argue that Vioxx usage accelerated in 1999 and that the full 2000 rate was reached late in 1999. Perhaps. However, let’s assume that it is true. This means that very few 1999 Vioxx users would have been taking it for 4-6 months (or even 3 months) in 1999. Let’s go further and drop any risk onset delay and assume a purely linear model (incremental risks start on day one). That makes the total Vioxx risk equal to the number of prescriptions (which quadrupled between 1999 and 2000). This falsifies the 1999 Vioxx thesis immediately.

    However, let’s go further and assume a very front loaded risk profile (you either die quickly or you don’t die at all) and that Vioxx prescriptions accelerated to the 2000 rate by the end of 1999. With that combination of assumptions, the incremental mortality should have been in 1999. However, it also means that in 2004 there was no one left to die. Clearly Vioxx wasn’t adding a lot of new users by 2004 (sales had been declining since 2001). With a front loaded model, the Vioxx recall should not have reduced 2004 mortality.