How to avoid becoming a casualty of the other Drug War — for profits at the expense of your health:

A striking feature of modern medicine is the debilitating and lethal consequences of adverse drug reactions (ADRs), which rank as one of the top 10 causes of death and illness in the developed world

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With an estimated 2 to 4 million serious injuries each year, drug therapy stands as one of the most significant perils to health resulting from human activity.

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833,076 adverse drug events reported to the U.S. Food and Drug Administration during 2014. …Although drug adverse effects are estimated to account for 100,000 to 200,000 patient deaths and 1 to 2 million hospitalizations each year

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[O]ne in every five [new drugs] eventually caused enough serious harm in patients to warrant a severe warning or withdrawal from the market

Drug companies are supposed to prove safety and efficacy in multiple clinical trials. These are then reviewed by the FDA before approval. So why do we have such a high casualty rate? Cheating.

Falsifying the Scientific Record

There is good evidence of selective outcome reporting in published reports of randomized trials…. We examined reporting practices for trials of gabapentin …We identified 20 clinical trials for which internal documents were available … of these trials, 12 were reported in publications.

A company is not going to ignore a good result. The 8 trials that went unreported were hopeless failures and swept under the rug.

For 8 of the 12 reported trials, the primary outcome defined in the published report differed from that described in the protocol. …
For a trial result to be valid, the criterion for success has to be specified ahead of time. If you can pick and choose after the fact, that is no different from shooting an arrow at the side of a barn and painting a target where it lands. So only 4 of the 20 trials actually succeeded.

For a trial to be regarded a success, there must no more than a 1 in 20 likelihood of a positive result due to chance. If you design a trial to this minimum standard, and run 20 trials, the likelihood that at least one of them will have a successful outcome by accident is 64%. So the sponsor left little to chance. If the medication actually worked as claimed, the vast majority of the 20 trials would have been successes.

But selective reporting is by no means the only method of falsifying the evidence. If the sponsor is designing a “me too” drug, it is necessary to show the drug is at least as good as the competition:

[S]ome physicians had so far forgotten their professional ethics that, again at the behest of their sponsors, they were getting the results their sponsors wanted in drug trials by hobbling the other horse in the race, the competitor’s drug, which in the trials was administered in the wrong dose by the wrong route

Or better yet:

Empirical evidence suggests that … industry-sponsored trials are more likely to compare the sponsored intervention against an inactive or straw man comparator.

If companies are going to cheat when it comes to efficacy, should we expect any better with regard to safety?

GlaxoSmithKline would not face prosecution for deliberately withholding trial data, which revealed not only that Seroxat was ineffective at treating childhood depression but also that it increased the risk of suicidal behaviour in this patient group. The decision not to prosecute followed a four and a half year investigation and was taken on the grounds that the law at the relevant time was insufficiently clear.

A depressed child is unlikely to recognize a drug is causing his or her suicidal impulses, and is in a poor position to refuse the medication. The emotional devastation wreaked upon a parent who has lost a child is horrific. Selling an ineffective drug that instead increases suicide risk among children is about as low as one could possibly go. Ethics? If a human were to behave like a corporation, he or she would be regarded as a sociopath. Unlike corporeal persons, corporate persons have no empathy, compassion, remorse nor fear of punishment. Pharmas will strive to hide any risk and claim any benefit that they can get away with.

What about whistleblowers?
Meanwhile sponsoring companies threatened the researchers to prevent them from publishing unfavorable results.

They had signed non-disclosure agreements. To complete the picture:
Metaanalysis is a rigorous technique whereby all the literature concerning a particular drug could … be identified, and … the efficacy of the drug in all comparable high quality trials, could be worked out… it was found that companies were paying physician scientists to publish the same results of the same trials in different journals, under different authors’ names, with no crossreferencing.
Since they were also paying scientists to publish only the positive results, and bury the negative ones, this systematic obfuscation had the effect of creating artificial scientific support for a drug, both before regulatory agencies, and, of course, to impress the prescribing physician.

And afterward:

Post-Marketing Surveillance

As for post-market surveillance — “the single most important function…for protecting the public against the dangers of harmful drugs” — it is put largely in the hands of the manufacturers

What do drug companies do with this awesome responsibility? Fox, meet henhouse...

Damage Control After Approval

Damage control for them means damage to us. Their tactics are:

• Once serious adverse effects become known, minimize the risk.
• Place convenient, seemingly impartial and well-referenced summaries in places doctors will look
• Persuade patients to take, and keep taking the offending drug in spite of risks and warning signs.

Their means toward this end is to employ physician “experts” to write convenient, comprehensive, well-referenced reviews of the medication. Convenient for a busy doctor because everything s/he needs to know is all in one place instead of having to chase through the literature to find different details. These seemingly respectable pieces show up in seemingly respectable places, like Mayo Clinic and Medscape.

As an example, let’s try Google Scholar to search for “adverse effects” and Fosamax. The first result is an impressive looking article from Mayo clinic. Google thinks this is the most relevant result because it is the most frequently visited. Clicking on it, we get this full text for free instead of an extortionate fee. Now heading to Subtrochanteric Femoral [i.e.,hip] Fractures:

Although these bisphosphonate-associated fractures are uncommon, several case reports have described some of their typical clinical features. .... Recently, the association between such fractures and bisphosphonates has been questioned, and these fractures were suggested to be merely an uncommon subtype of osteoporotic femur fracture

Oh OK, uncommon. Just a few case reports, maybe not drug related at all. Nothing to see here (to be continued).

Uncommon? Underreported:

It is estimated that as few as 5% of all adverse drug reactions are reported to appropriate agencies. Underreporting is likely related to ... failure to recognize adverse drug reactions when they occur. Children are particularly vulnerable.

Underreported because physicians think drugs are safe:

Factors associated with under-reporting [drug adverse events] were ...indifference (the one case that an individual doctor might see could not contribute to medical knowledge) and insecurity (it is nearly impossible to determine whether or not a drug is responsible for a particular adverse reaction) in 67%; and complacency (only safe drugs are allowed on the market) in 47% of studies.

Damage Prevention

We have seen that the record is thick with false information. If you are so inclined, there is a wealth of information to be found at Google Scholar. Be properly skeptical of the vast number of studies praising a drug’s benefits and minimizing its drawbacks. If you are looking for adverse effects there, best to search on the drug class, for example, bisphosphonates for Fosamax. If you don’t know what effect you are looking for, use “adverse effects”. Then search individually on a specific adverse effect. Exactly how to search in this manner is narrated in the Statin research below.

Always Check the FDA label — you can get this via a web search for “FDA label” and the drug name. Pay special attention to listings of adverse effects, drug interactions, whether to take with or without food, and the effect of mineral supplements.

This is not enough though, because information regarding important adverse effects is likely to have been concealed by the manufacturer. At the other extreme, there are alarmists out there with websites long on outrage and short on facts. This will not do either.

Useful sites:

askapatient.com— Compiles patients’ ratings of medications on a scale of 1-5 and presents their individual commentaries. Compares ratings of different medications in the same class. Provides a summary of adverse events reported to FDA. Excellent site. Only caution: in some cases the average rating is derived from a small number of individuals. (Originally suggested by SSK in the comments)

patientsville.com — Lists side effects by frequency of patient reports, by individual medication. It also displays individual patient reports. The downsides: it is extremely slow, and the user interface is uneven. It takes scrolling down to get side effects by frequency. Note that this does not tell you how severe the side effect is. In the case of “femur fracture” this is self-evident, but in the case of myalgia it is not. It looks like they are using reports submitted to the FDA as well as reports submitted to the site.

Attorney websites are a good source of information. Attorneys will not hide any problems, nor will they make alarmist claims that would not be actionable:

• Drugwatch — They have a list of drugs and adverse effects. Not comprehensive — none of these attorney sites are. Some additional information showed up via google site search.
• Lawyers and Settlements — They’ve got lists of lawsuits, past and present. They set forth the allegations in the suit, and the result if the suit has been decided.
• American Injury Attorney Group > Lawsuits > Bad Drugs — A list of drug lawsuits. They tell you what the drugs did to cause the suit.

Consumer Reports has a list of 10 drugs to avoid.

Here is a database intended for doctors that lets you search for drugs indexed by adverse reaction. From their front page:

The sole fact that the patient knows that ADRs [adverse Drug Reactions] can occur is enough to discourage the patient let alone if the individual should actually experience such a reaction during therapy

The implication being the doctor should not warn patients of possible adverse effects, and should minimize them if reported. We already know that some physicians believe only safe drugs are allowed on the market. This is bad news. For some medications the onset of certain side effects is a dire event. In such cases the medication should be stopped immediately lest really serious damage ensue. Two examples are:

• Fluoroquinolones (Cipro, Levaquin, etc.) — tendinitis or neurological symptoms
• Dopamine Agonists (medications for Parkinson’s and Restless Leg Syndrome) — lightheadedness or impulse control disorder (established users must taper slowly)

Impulse control disorder? That refers to compulsive gambling, sexuality, or eating. Some patients who had previously been responsible citizens have lost everything due to dopamine agonist induced compulsive gambling. Many patients did not realize the drug was causing it.

​So when taking a new medication, be on the alert for any adverse effect. It may occur immediately, or be delayed for quite some time. If you experience some new symptom, get to work and search askapatient, patientsville, Google Scholar and the web to see if the medication may be the cause, and the possible outcomes. In any event, ask your doctor for a different medication. If you can quit the medication safely, do so.

Just Say No to Bad Drugs

BISPHOSPHONATES

(Fosamax, Reclast, Zometa, Actonel, Boniva, Aredia)

[S]ubtrochanteric and diaphyseal fractures occurred at a rate of 13 per 10,000 patient-years in untreated women and 31 per 10,000 patient-years in women receiving alendronate [Fosamax]

The subtrochanteric is the top of the femur near where it enters the hip socket. If it breaks, this is a hip fracture. The diaphyseal is also the femur but lower down. So according to this study, Fosamax more than doubles hip fracture risk. The authors go on to speculate that maybe the increased risk is due to osteoporosis in Fosamax patients, Hence the comment in the whitewash posted at Mayo Clinic:

these fractures were suggested to be merely an uncommon subtype of osteoporotic femur fracture

Fosamax was supposed to solve that problem. Yet the FDA label says:

FOSAMAX increases bone mass and reduces the incidence of fractures, including those of the hip and spine

It does increase bone mass but that is not the same as bone strength. How did this happen? From that same label:

In the Three-Year Study ...fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on FOSAMAX, p=0.047.

The cutoff is pThe most commonly reported Fosamax side effects...
Femur Fracture (5674)
Anxiety (3177)
Osteonecrosis (2820)
Oh yeah, jaw necrosis. As noted at the link you won’t do better with any of the other bisphosphonates, either.

What to do to prevent hip fractures? Per the previous articles in this series, take vitamins K1 & K2, plus vitamin D, and a couple of other essential nutrients.

What vitamins K and D do for you [25(OH)D is Vitamin D] :

[A] 50 % higher risk of hip fracture was observed in subjects with both low vitamin K1 and 25(OH)D compared with subjects with high vitamin K1 and 25(OH)D (HR 1.50, 95 % CI 1.18–1.90).

In other words, with high levels of K and D the hip fracture risk is only 67% (1/1.50) of the risk at low levels. In medspeak this is a hazard ratio of .67. Note how the data was framed as the dangers of low levels of vitamins rather than the benefits of high levels.

How about alleged improvement due to Fosamax? According to this meta analysis, the risk ratio for hip fracture, according to some published studies, was .63-.65. For the other bisphosphonates it ranged from .58-.73. Even if these numbers are accurate, you will do as well with vitamins, without the risks.

The reader may have noted that one of these studies used relative risk (RR) and the other, hazard ratio (HR). What is the difference?

The Cox proportional hazards model is an appealing analytic method because it is both powerful and flexible. The hazard ratio, which is derived from this model, provides a statistical test of treatment efficacy and an estimate of relative risk of events of interest to clinicians

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HR is an estimate of RR, so they are comparable measures.

STATINS

The most popular statin is Crestor (rosuvastatin), the 13th most prescribed drug in the US. At patientsville the most common side effect is myalgia, muscle pain. A search of Google Scholar using “Crestor myalgia and ‘adverse effect’ “, since 2012, finds this PLoS One study:

We examined rhabdomyolysis, but also included less devastating muscle-related side effects. These are important in their own right, due to their greater frequency, significant effects on quality of life, and impact on statin therapy non-compliance.…

Appreciable occurrences of muscle-related side effects were not uncovered during prerelease clinical testing of statins.

Oh, what a surprise.

Accordingly, side effects, including a range of muscle and tendon disorders extending from myalgia to life-threatening rhabdomyolysis, became evident primarily after the drugs won FDA approval. ... Exemplifying this, the elevated occurrence of rhabdomyolysis with cerivastatin (Baycol) culminated in numerous deaths and the withdrawal of cerivastatin from the market. More recently, the FDA announced new safety recommendations for high dose simvastatin, citing an “increased risk of myopathy when using the 80 mg dose of simvastatin.” This warning was issued only after many years of clinical use of simvastatin, indeed among the best-selling prescription drugs, and five years after its loss of patent protection.

Rhabdomyolysis?

Rhabdomyolysis is a serious syndrome due to a direct or indirect muscle injury. It results from the death of muscle fibers and release of their contents into the bloodstream. This can lead to complications such as renal (kidney) failure

Also:

Immune-mediated necrotizing myopathy (IMNM) is characterized by the predominant presence of necrotic muscle fibres in muscle biopsy and variable response to immunosuppressive treatment.…

Our data show an increasing incidence of IMNM, which is mainly accounted for by anti-HMGCR-positive IMNM associated with the use of statins.

What do we get for all this risk? Searching on statin benefits, via Google Scholar since 2012, should be a slam dunk for the Pharma team. First up:

Cardiovascular benefits and diabetes risks of statin therapy in primary prevention

In view of evidence that statin therapy increases risk of diabetes, the balance of benefit and risk of these drugs in primary prevention has become controversial….

Oh, diabetes risk too. After further experimentation, searching on “statin AROUND benefit ‘cardiovascular mortality risk’ “ we find a meta-analysis of statin benefit, the gold standard of evidence:

The aim of this study was to evaluate the long-term efficacy and safety of statin treatment by performing a meta-analysis of statin [trials] with extended follow-up beyond 6 years…..

Over the entire 6.7–14.7 years of follow-up, a significant reduction in the rates of all-cause mortality (relative risk 0.90), cardiovascular mortality (0.87) ... was observed in favour of the original statin group.

Let’s compare to Vitamin K:

[I]ndividuals who increased their intake of [K1] or [K2] during follow-up had a lower risk of cancer (HR: 0.64 and HR: 0.41 respectively) and all-cause mortality (HR: 0.57 and HR: 0.55 respectively) than individuals who decreased or did not change their intake. Also, individuals who increased their intake of dietary [K1] had a lower risk of cardiovascular mortality risk (HR: 0.52) [confidence intervals removed for clarity]

Increasing your vitamin K, you get a 44% reduction in all-cause mortality risk (HR 0.56) versus 10% with statins (RR .90). Likewise, with vitamin K, you get a 48% reduction in cardiovascular mortality risk (HR .52) versus 13% with statins (RR .87). All without the risking death of muscle fibers, or diabetes. Plus with K you get the reduction in hip fracture risk as well.

Why are statins and bisphosphonates even on the market? Why are doctors not checking everyone’s levels of vitmains D and K? Profit driven medicine courtesy of Big Pharma.

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FLUOROQUINOLONES

Fluoroquinolones (“FQs”) are antibiotics that can be life-saving, if you really need them. All too often they are prescribed casually, where an antibiotic may not even be needed, or if an antibiotic is needed, where something less toxic will do.

FQs can be identified by the ending of -floxacin in the generic name. Members of this class include Cipro, Levaquin, and Avelox. So what goes wrong?

Lets’ take a look at Cipro. We don’t have to look far for this one — the FDA label has a black box warning right at the top (Bolding NOT added):

WARNING: Fluoroquinolones, including CIPRO®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (See WARNINGS).
How serious is this? Let’s put it this way: Fosamax and Crestor did not get the black box.

in a large population-based case control analysis, patients treated with FQs exhibited a substantially increased risk of developing tendon disorders overall (1.7-fold), tendon rupture (1.3-fold), and ATR [achilles tendon rupture] (4.1-fold).
Neuropathy is another problem:

We identified 6,226 cases and 24,904 controls. Current users of FQs were at a higher risk of developing PN [peripheral neuropathy] (RR = 1.83). Current new users had the highest risk (RR = 2.07)
Further detail can be found in How We Can Halt The Cipro & Levaquin Catastrophe: The Worst Medication Disaster In U.S. History. This book is by an MD detailing his knowledge and research after a career of treating “floxed” patients.

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Well, that’s all for now. There’s more, which will have to wait for another day.