The authors then categorize patients based on how they make health care decisions, such as “minimalists”, who believe “less is more” (that’s me!), and “believers”, who believe there is a cure for everything, and then the “doubters”, “who worry that almost any treatment will be worse than the disease”. Then comes the categorization of “experts” being fitted into these categories, such as “the Federal Preventive Services Task force as “minimalists” and “doubters”, and that is why experts can look at the data and have differing opinions. The authors then make their point about the uncertainty of “best-evidence” saying, “No one can say with certainty who will benefit by taking a certain drug and who will not”.

Then there is the discussion about the delivery model of health care and how it’s changed. “Medical care used to be paternalism: A doctor dictated what was to be done and the patient complied. This model has largely been abandoned, but Democrats and Republicans are offering a new form of paternalism.”  I agree with the authors when they say treatement decisions should be made between doctor and patient, since everyone has differing circumstances with which they are confronted, and differing needs which alters their priorities, and a “cookie-cutter” style approach doesn’t always meet the needs of the person. However, something must be done to lower health care costs since we spend the most in the U.S., but don’t get the most in return, so I see clearly that certain restrictions and guidelines need to be applied in order to sustain health care services to all. We just need to determine what is the absolute “best-evidence” to start applying and measure the benefits of its application.

I responded to the question a few years back when someone asked me what I do and I said, “My job is to get as close to  the truth as is possible”, and that is what I have been doing for several years, gathering evidence, analyzing it, and determining when “evidence” is not the “best-evidence”, and sometimes downright false, and what evidence is, without a doubt, solid. What I have come to know to be true is that we are causing harm by misusing medications in older adults, to the degree that adverse drug events is now the 4th or 5th leading cause of death by disease and forecast to race to the top of the charts within 10 years. It is also clear that application of the “best-evidence” regarding the appropriate use of medications in older adults can prevent the majority of them from occurring, and lower costs by lowering health care utilization and avoiding complications. We just need to find a way to collaborate as health care providers, with the person at the center, and try to keep the best-evidence in front of us.

Here is the link to the WSJ article.

http://online.wsj.com/article/SB10001424052702303404704577311641531125820.html

Some of the more specific findings from the studies were: patient and healthcare professional reports are of similar quality; there was some evidence that different ADRs are reported; new ADRs are reported; reported symptoms to SSRI antidepressants, e.g. Zoloft, Celexa, Lexapro, Prozac, are not found in health care professional reports, implying a reluctance to report unusual psychiatric symptoms to physicians; some evidence that patients report ADR symptoms quicker; no evidence that reports result in distraction from signal detection, meaning they do not distract from ADR “flags” and overload the ADR reporting system.

In all, patient-reporting of ADRs is a reliable method for detecting probable ADRs which can lead to mitigating them and improving quality of life, and avoid unnecessary utilization of health care resources, in addition to lessening the risk for patient harms. However, in my experience, if people are not educated on what side-effects to monitor for, and if physicians do not acknowledge that ADRs are possibly occurring, especially some of the more unusual ADRs, then a large percentage are not addressed and lead to negative outcomes. Several other studies have validated this finding. Lastly, specific questions asked of the patient that may elucidate if an ADR is occurring should be included in every medication review and office visit. The reliability of this technique is greater than what one might think.

My quest for a solid explanation started some time ago when reported findings from a couple studies made no sense at all, and I read the statements of “..after adjusting for confounding variables or risk factors..”. I first verified my suspicion in Dr. James DeMuth’s book on pharmaceutical statistics where he states we can not adjust for confounding variables and assume the conclusion is a direct cause and effect. All we can state is a correlation exists, but some authors seem to go much farther in drawing conclusions. In this article, by Dr. John Concato, et al, published in Annals of Internal Medicine, 1993;118:201-210, the author reviews common problems with the use of multivariable analyses, the first being the over-fitting of data, in which too few sample outcomes are applied to a model, and then correlations drawn from those too few outcomes. Other problems involve non-conformity to a linear gradient. For example, the impact of left ventricular ejection fraction on negative outcomes not being linear and is dependent upon where the initial ejection fraction was measured at baseline, e.g. a reduction from 40% to 30% has much lower risk as compared to a reduction from 25% to 15%.

Another problem is what the author says is a “violation of proportional hazards”, in which the risk or hazard of an independent variable is assumed to be constantly proportional. This false assumption is probably where I became suspicious, that a simple “adjusting for confounding variables” assumes all variables to be constant and exist in a simple relationship of direct correlation. The main point I make is that many statistical analyses have limitations and become more limited in their usefulness when they are not applied correctly thereby leading to incorrect conclusions.

Isn’t it true, that on any given day, we can read the summary of a research article which states that a treatment is associated with a negative outcome, after having adjusted for confounding factors, etc. And then one month later we read the opposite results from another study. It begs the question, which article is most accurate in their conclusions, if either? The use of statistics in medical research has accelerated in the last twenty years but not without concerns over the quality of its applications. I, like most human beings, tend to take things at face value. But as more findings hit the news I find myself having to employ discipline and not form any opinion until a detailed analysis of the study can be made to determine if, in fact, the purported conclusions have any meaning at all. The other application of this principle is for the lay person, no matter how educated, do not react to any information in the news.

In the more recent study, increasing age, number of medications and these four classes of drugs were most strongly associated with ADEs leading to emergency hospitalizations. Other medication categories that were involved in a large number of emergency hospitalizations were: cardiovascular drugs, antibiotics, sedative hypnotics, anticonvulsants, opioid analgesics, and Beer’s list medications. When factoring digoxin out of the Beer’s list admissions the percentage of admissions from Beer’s list drugs dropped nearly in half. It was also interesting that in 47% of cases the dose of digoxin was appropriate, according to Beer’s criteria. This means the dose of digoxin alone is not a completely effective screening criterion, but perhaps more frequent monitoring and drug interactions may play a role.

Speaking of drug interactions, this study did not report on the role that drug interactions have in leading to ADEs in older adults. There are recent data that list just a few critical drug interactions that lead to emergency room visits and hospitalizations in older adults. You can learn about those drug interactions at my post: http://elderdrugs.com/2010/11/adding-a-new-medication-watch-out-for-these-drug-interactions/
With regard to the anti-diabetic medications insulin and oral hypoglycemics, the implication is strong that routine monitoring and engagement of the person with diabetes is critical in catching downward trends of blood glucose in order to prevent severe hypoglycemia from occurring. As a diabetes educator I have always preached that the person with diabetes who is actively engaged in their own health is more likely to be successful, as opposed to the person who does not take an active role in managing their diabetes.

In conclusion, this study confirms previous studies and the role that just a few medication classes play in causing a large percentage of ER visits and hospitalizations in older adults. However, we mustn’t forget the large percentage of ADEs that lead to functional or cognitive impairment that we may just “chalk up” to aging. With the aging body less able to tolerate the insult from multiple medications, and with so many possible ADEs that can occur in those with complex medication regimens, anything less than a comprehensive medication review and development of a structured medication plan will fall short of the goal. So I advise to look at the entire body of literature and make your comprehensive medication review checklist in order to not miss some key contributors to ADEs in the older adult.

Findings

Number of Medications and Co-morbidity

Of 22 studies reviewed the two most commonly cited risk factors for ADEs are number of medications, and number of co-morbid conditions. Most studies (N=5) cite 5 or more medications as being the most reliable risk factor for predicting an ADE, one study said 3, others just reported a rising correlation with more medications, e.g. 10% increase in risk for each additional medication. With regard to co-morbidities, there were several methods of reporting this, three by number of diagnoses, two by the Charlson co-morbidity index, and a couple by disability index or worsening health status. Not all studies had a report of number of medications or chronic conditions, and two said there was no correlation with number of medications and one study cited no correlation with number of diagnoses.

Gender, Age, Transitions in care

There was no congruency with gender, with one saying none, and two correlated with being female and two with being male. Only three studies reported on transitions in care, two saying there was a correlation and one saying no correlation. Age also had inconsistent reporting with four studies saying no correlation and three saying there was a correlation.

Medication Classes

For specific medication classes there is a huge disparity between studies with studies not always reporting the same medication classes as other studies, and some studies contradicting the positive correlation of a particular medication class from other studies. In general, the number of positive correlations from these studies by medication class is as follows: antibiotics (6 studies); antipsychotics (5); antidepressants (8); benzodiazepines (6); cardiovascular meds (11); opiates (5); anti-epileptics (1); cardiac glycosides (6); insulin (5); oral hypoglycemics (5); diuretics (10); warfarin (10); NSAIDs (8); ACE inhibitors (3); beta-blockers (4); anti-platelets (2); electrolytes (2); PIMs (3); steroids (3); and Parkinson’s medications (1).

Other considerations: Drug interactions, ADE history, lack of monitoring

One must consider that a reported ADE by medication class could have actually resulted from a drug interaction that went undetected or not known at the time. For example, SSRIs and NSAIDs are strongly correlated with risk for GI bleeding, yet if not known it would most likely be reported as NSAID-induced. Also, this may tie into another risk factor found in a couple of other studies and that is the recent addition of medications, or medication changes, as a predictor of ADE risk. That would link to the concept that drug interactions are largely responsible for ADEs with one study saying 26% of all ADEs are drug interaction related. Another consideration is that there are other risk factors to take into account such as history of an ADE. One Australian study verified this as a predictor for a repeat ADE. Also, many of the medication classes where ADEs are found to commonly occur imply that more frequent monitoring may have prevented those ADEs. Thus, lack of monitoring is a risk factor for ADEs, as reported in other studies, and may account for up to 40% of all ADEs.

Summary

The most reliable predictors of ADEs are number of medications and co-morbidity and not necessarily specific classes of medications. Yet there are many confounding factors that can lead to ADEs therefore a comprehensive approach to detection is most likely to detect all areas of risk, which then leads to targeting areas for interventions to prevent ADEs. Understanding the nuances of ADE causation in older adults is necessary in order to make the largest impact on ADE prevention, anything less will not necessarily result in a significant reduction of occurrence of this 5^th leading cause of death by disease, albeit a man-made disease.

“Two factors, polypharmacy and polyprescribers, appear to be strongly associated with the increased exposure of elderly patients to drug-drug interactions (DDIs) and potentially inappropriate medications (PIMs).”

It has been known for awhile that the number of drugs taken by an older adult are linearly correlated with the risk for an ADE. We also know that when multiple prescribers are involved there is a tendency for one prescriber to not work from an updated med-list and not necessarily update the primary care provider, thereby leading to possible duplicate therapies and additive side-effect potential from multiple medications. One other factor that we need to consider is the filling of prescriptions at more than one pharmacy. Without an accurate medication history it is not possible for the dispensing pharmacist to detect potentially serious DDIs or duplicate therapies. One other thought is that the authors define polypharmacy as just taking multiple medications. However, it may be best to consider the definition to be the use of multiple medications whereas not all of the medications are appropriate nor have an adequate monitoring plan thereby increasing the risk for serious harm. Many people can take multiple medications but do just fine and not experience an ADE, because the drugs selected for use are not PIMs or there is an adequate monitoring plan in place.

“Many drugs adversely affect older patients by leading to falls, fractures, and functional and cognitive decline, and sometimes to unnecessary and costly hospitalizations and nursing home placements.”

If 20-25% of ADEs lead to hospitalization in the older adult population, then it stands to reason that preventing 50% of these ADEs can significantly lower costs. If the cumulative evidence is applied to reduce medication utilization AND minimize the risk for ADEs, then it is modeled to predict significant reduced health care expenditures on the drug side of the equation in addition to reducing costs by reducing health care system utilization.

“The addition of each new drug to a treatment regimen increases the risk of an ADE. For instance, in an ambulatory care setting in 2003, Gandhi et al. determined that the mean numbers of ADEs per patient increased by 10% for each additional medication.”

Oh so true! Some data are reflected to state: “If you take 5 to 8 medications you are at 50% risk for an ADE, and if you take more than 8 medications you are at 100% risk for an ADE.” This is where the key principle stated here by the authors is clearly reflected in the data. The more the drugs = the greater the risk. So, in effect aren’t we then being driven to determine where we can minimize medication use? Doron Garfinkel published in Archives of Internal Medicine in October 2010 about using specific criteria to safely eliminate almost 50% of medications taken by 72 older adults in the 80-something plus cohort. Function and overall well-being improved, as did measures of cognition, yet with no harms noted.

“The manifestation of ADEs in elderly patients may not be obvious because the effects can be similar to problems frequently experienced by elderly persons, such as increased frequency of falls, excessive sedation, increased confusion, urinary retention, decreased oral intake, or general failure to thrive. These manifestations, when not recognized as drug-related, can result in the physician’s prescribing another medication to mitigate the ADE.”

Also known as the “prescribing cascade”, where a drug is added to treat the side-effect from another drug where the side-effect from the other drug was not recognized as such. This is not uncommon. Here’s an uncommon but documented scenario: I start a statin, say Zocor for high cholesterol. I then develop memory loss a few weeks later, which is assumed to be a “normal part of aging” seeing as how I’m 87. The physician, along with support form my wife, then adds Aricept (donepezil) so that I am now taking two drugs, of which it can be debated in many circumstances if the statin is needed in the first place. Aricept and similar memory health drugs are known to cause urinary incontinence in about 10-20% of users. Therefore, since I’m now peeing in my pants it’s time to add a bladder health drug, say Detrol or Ditropan. Either of these two drugs blocks the beneficial effects of Aricept, and may also cause cognitive impairment, dizziness, sedation, constipation, dry mouth, and so on. So there we have three drugs at about $5000 per year with two, for sure, not being needed, and with the third possibly also not being needed, all in an attempt to try and lower a cholesterol number in someone without any history of heart disease and limited life expectancy. You want lower costs? Then start with medication minimization.

“ADEs can be minimized and their occurrence can be managed but not totally eliminated.”

Yes, this is true. Prevention estimates range from 26% to 95%. The estimate I have seen most frequently and that makes most sense is that about 50% of ADEs can be prevented. That might cut the mortality rate of this “man-made disease” in half. By the way, the mortality rate from ADEs  makes it the 5^th leading cause of death by disease. It can climb to number one in about 10 years if there is no change in how we practice our respective health care professions of medicine, pharmacy, nursing, psychiatry, and all the others involved in the medication-use process. Oh, and don’t forget the person at the center here, the one who is paramount in helping solve this problem. If we listen to complaints, respond to them with our intuitive expertise, and the evidence, we can mitigate or prevent a large number of these ADEs. Many self-reported ADEs by the patient go untreated or ignored, yet I know of two studies that showed how fairly accurate people are at detecting an ADE, but not all types.

“Pharmacists are a critical part of this process, in ensuring proper medication use in the elderly through medication counseling, medication therapy management services, and use of drug utilization evaluations to ensure that medications are being prescribed and monitored appropriately. Pharmacists can also work in conjunction with physicians to decrease ADEs by obtaining an accurate medication and medical history, aligning medications with disease states, identifying medications that may be treating side-effects of another medication, and ensuring medication reconciliation at every care transition if new medications are ordered or existing orders are rewritten. Prescribers should avoid prescribing inappropriate medications for the elderly if possible and use drug therapy only when it is essential, helping to ensure maximum therapeutic benefit, minimal side-effects and overall compliance.”

Many parts in the above paragraph may be correct. However, I don’t see where the reimbursement system incentivizes pharmacists to do all of the above, especially in the community where 95% of older adults reside. We would need to change the incentive in our health care system to reward quality and outcomes while reducing cost. However, that’s much further in the future. Right now every community pharmacy outside of a health care system is incentivized by “profit per prescription” in order to survive, which is alright but not linked to the appropriate incentive to reward quality outcomes in preventing and mitigating ADEs. However, in some health systems  there are pharmacists placed at the appropriate portal, reviewing and reconciling medications and making just such an impact. But we need this done en masse throughout our communities, because if we continue to do business as usual we’ll get the same results.

One additional method that may be hugely impacting is utilizing the most comprehensive, and sensitive, medication screening tool at the point of prescribing. Almost 50% of ADEs start at the point of prescribing, not even considering how many start there because of the absence of an adequate monitoring plan, which is estimated at 40%. But I must make a point, in that you need the expertise that can help design that tool in order for it to make an impact. This then segues into the term I threw out there before, called “intuitive expertise”. A wonderful article in NY Times, October 23, 2011 written by Daniel Kahneman, speaks to the concept of “being an expert”. I don’t want to get into the details as I’ve gone on long enough, but I know this guy is right on. He knows when someone who proclaims to be an expert is NOT an expert. Quoting Daniel, “Many people exercise their judgment with evident confidence, sometimes priding themselves on the power of their intuition. In a world rife with illusions of validity and skill, can we trust them? How do we distinguish the justified confidence of experts from the sincere overconfidence of professionals who do not know they are out of their depth?”

What I find amusing about Daniel Kahneman’s article is that he studied the success of professional investors of large mutual funds and showed how those overconfident, overbearing and bullish fund managers were no better than average in their returns. But by the way he heard these fund managers speak you’d think they were the real experts. In closing, I quote the author: “True intuitive expertise is learned from prolonged experience with good feedback on mistakes.” I find that learning about ADEs in older adults requires years of experience, with listening to and observing older adults, and pouring through the literature to eventually establish validity. Some of the methods of study design and statistical methods used in the published literature are filled with errors and come to incorrect conclusions, thereby misleading health care professionals and the lay people. For example, one can reference a “study” that concluded calcium supplements are associated with an increased risk of death. Then a year later another study finds that other supplements, but not calcium, are associated with a higher risk of death. Or, two studies come to the opposite conclusion regarding SSRI’s (Prozac, Zoloft, etc) and the risk for GI bleeding. Do you know which conclusions are correct, if any?

The 8th stage is where the older adult reflects upon their life and either becomes satisfied or develops a sense that it was not a life worth living, hence Despair. Erikson is quoted as saying: “Despair expresses the feeling that time is now short, too short for the attempt to start another life and to try out alternate roads…” He also states that we do have one firm foothold in this stage to fall back on and that is “Basic trust”, and “life without it is simply unthinkable.” He states that Wisdom is the healthy product of the 8th stage where we can develop “an informed and detached concern with life in the face of death itself”. We must also note that those in their later years, long past their “Generative years”, still need a purpose and involvement in society. How can they still be useful and give back? That is the question many older adults have and probably why so many volunteer to form a labor force of unpaid caregivers and doers for others in need, truly purposeful living. However, there is another stage, the 9th.

Erikson also points out that “I am persuaded that if elders can come to terms with the dystonic elements in their life experiences in the 9th stage, they may successfully make headway on the path leading to gerotranscendence.” What is gerotranscendence? Principles regarding gerotranscendence from the Erikson’s book “The Life Cycle Completed” are: Letting go of the material things; gaining the wisdom of humility; defining ourselves by what we give back; to rise above, outdo, go beyond, independent of the universe and time; to leave behind those things we can not carry any longer as they are  too heavy a burden; gaining new spiritual gifts. It’s as if the the older adult in the 9th stage transcends to be a playful child once again, not caring about the material things nor the false pretense of power and stature. Sounds like a nice place to be!

So what’s my point in bringing all this up? My perspective is that the last stage gives us the opportunity to find peace with ourselves and transcend into a different person who is at peace with the world. A loving, caring human being truly of value to the world. That would be by my definition of “successful aging”.

Neurology has also published studies that focus on reducing the risk of developing Alzheimer’s disease by treating diabetes. Researchers refer to diabetes in this subset of the population as Type 3 diabetes where it is strongly linked with “neuroaging”, a premature aging of the brain due to the metabolic and cardiovascular effects of diabetes. Also some time ago I read an Italian study that showed how nursing home admissions for Alzheimer’s disease were greatly reduced in those with hypertension when treated with an antihypertensive drug ramipril. What this says is that cardiovascular damage from these conditions is strongly linked to the development of dementia. It also suggests that if we can identify these risks then we can intervene with established treatments to slow the progression to full-blown dementia thereby aging in place.

Theories abound but what’s important is to understand the role of these risk factors and their potential for leading to dementia if left untreated. My observation in a large older adult cohort is that isolated systolic hypertension is rampant in as many at 33% of this population yet remains untreated. When you get screened for these risk factors, the next step would be to choose appropriate treatment and monitor that treatment in order to prevent adverse events from occurring. Please feel free to scan my previous posts on diabetes and neuroaging, isolated systolic hypertension and others on dementia.

All older adults (>65y/o) should have their vitamin D blood level checked by their physician. If it’s low, <30, they should be treated in order to get that blood level up to about 40.  Supplements may be needed to maintain that blood level over time. Vitamin D is an essential nutrient and many of us do not make enough due to inadequate sun exposure, along with the fact that this mechanism doesn’t work well as we get older. (NOTE: The IOM INCREASED the recommended daily amount of vitamin D to 800 units for older adults, a very conservative number, and set the upper limit at 4000units a day.) We recommend that older adults consider achieving daily intakes between 1000 and 2000 units if there are no reasons why they should not. Keep in mind, more processed foods are now supplemented with vitamin D so you need to count how much you normally take in each day, and don’t forget most multiple vitamins contain about 400 units. In summary, if you are an older adult who has had a low level, continue with what your doctor told you. Most older adults are safe with taking a daily supplement. An excellent review of the benefits of vitamin D can be found at the Linus Pauling Institute at Oregon State University. Here’s the link: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/index.html

Regarding calcium, the daily recommended intake for older adults is set in the report summary between 1200mg and 1500mg daily, which is what we normally recommend. There’s really no big deal into this report and you should appreciate the benefits to getting enough calcium and vitamin D each day as they are essential nutrients. The IOM report in brief is in PDF format in the link below.

http://www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf

Now for some guidance when it comes to health information in the news. Watch out! This is the worst source of information, the general news media. We have a link to the National Institute of Aging web site that provides you with a publication on how to interpret what’s in the news and other health research findings. Take a look at the link below. It will help you stay on track and not get so confused when you hear conflicting information.

http://www.nia.nih.gov/NR/rdonlyres/43F218DA-2188-40BC-90CE-7B740E8FA701/10421/Understanding_RiskWhat_Do_Those_Headlines_Really_M.pdf