A New Paradigm in Medicine and Health Care: 1. Current Paradigm (b)

[Dr Alain L Fymat]

A New Paradigm in Medicine and Health Care: 1. Current Paradigm (b)

In Part 1(a), I chose as a first example of the current paradigm of population medicine, the case of statins and statin combinations. I argued that:

 

(1) In place of the primary goal (or “real end point”), namely reducing the likelihood of a heart attack, stroke, or death, the pharmaceutical industry and the medical establishment use the intermediate measurement of lowering blood cholesterol (a “surrogate end point”) as a proxy for improving patient outcomes. The thesis is that for each percentage point that LDL is lowered, there would be about 1 percent reduction of heart attacks. Unfortunately, these two end points (blood cholesterol level and heart attack) do not track very closely.

 

(2) While reducing LDL levels (apparently by 18%-55%), increasing HDL levels (apparently by 5%-15%), and reducing triglycerides (apparently by 7%-30%) provide great satisfaction to doctors and patients alike, it gives them a false sense of safety.

 

(3) While most patients medicated with statins will have great blood test results, only one percent of them will actually benefit - those who have no history of heart disease but may, according to prevailing conventional norms, be at risk for developing such a condition. (The statin benefit will be greater in those individuals who have already manifested heart disease and, according to the pharmaco-medical establishment, could be justified in that situation.) In other words, the predominant benefit is a cosmetic one (normalizing a blood test that is out of a conventional range) at the risk of entailing side effects and adding to the current annual burden for prescription drugs ($ 300 billion in the U.S.).

 

(4) What about those patients for which statins have virtually no effect in lowering their LDL, raising their HDL, and lowering their triglycerides? The answer is apparently another surrogate end point of vague benefits in other unspecified health aspects.

 

(5) The holy grail of evidence-based medicine is the large-scale randomized, double-blind, placebo-controlled clinical trial performed under the most rigorous conditions. In the trial with Crestor (enrolled cohort of 17,800 patients), the reduction was 4% for the placebo group and 2% for the Crestor population, a statistically significant result. I raised the questions: If placebo has the greater benefit, who needs the statin with lifetime use and side effects? Is helping 2 out of every 100 patients who take lifelong Crestor worth it? How about the 98 other patients who do not derive a benefit but undergo the lifelong side effects of that drug? Further, is the risk of developing diabetes in 1 out of every 400 patients justified?

 

(6) Next, a meta-analysis by the Cochrane Collaboration of all the data from 14 randomized trials and over 34,000 patients concluded that “there was no net overall benefit of statins for patients without preexisting heart disease”. Thus, what is considered evidence-based medicine today is what is good for a large population, not for any particular individual.

 

(7) Lastly, if doctors do not prescribe statins in cases of elevated cholesterol levels, they may be given demerits by their hospital of affiliation or even be accused of medical malpractice for not adhering to “standards of care”.

 

Whereas much more could be said about statins and statin combinations, I would now like to proceed to a few other examples as these abound in population medicine.

 

Second Example: Prostate Specific Antigen (PSA) Blood Test

 

Prostate-specific antigen (PSA) is a glycoprotein enzyme encoded in humans by the kallikrein-3 (KLK3) gene. (Note: PSA is a misnomer in that though an antigen, it is not specific to the prostate and can be found in many male and female tissues.) It is produced in the epithelial cells of the prostate, and can be demonstrated in biopsy samples or other histological specimens using immunohistochemistry. It is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders. It remains present in prostate cells after they become malignant. Individual prostate cancer cells produce less PSA than healthy cells; the raised serum levels in prostate cancer patients is due to the greatly increased number of such cells, not their individual activity. However, in most cases of prostate cancer, the cells remain positive for the antigen, which can therefore be used to identify metastasis. However, since some high-grade prostate cancers may be entirely negative for PSA, histological analysis to identify such cases usually employs PSA in combination with other antibodies (PSAP, CD57).

 

PSA is not a unique indicator of prostate cancer, but may also detect prostatitis (prostate inflammation) or benign prostatic hyperplasia (BPH, prostate anomalous growth). The test guidelines are set forth below:

 

 

• The United States Preventive Services Task Force (USPSTF, 2012) does not recommend PSA screening noting that: (a) PSA-based screening results in small or no reduction in prostate cancer-specific mortality; (b) It is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary; (c) "[t]he potential benefit does not outweigh the expected harms (false positives, biopsy pain, and other complications)" in patients not already diagnosed or being treated for prostate cancer;

• The test may result in “over-diagnosis” and “over-treatment” because "most prostate cancer is asymptomatic for life"; (b) Treatments involve risks of complications: for every 1,000 men screened, 29 will experience erectile dysfunction, 18 will suffer urinary incontinence or impotence (erectile dysfunction), 2 will have serious cardiovascular events, 1 will suffer pulmonary embolus or deep venous thrombosis, and 1 perioperative death. and (c) The "potential benefit does not outweigh the expected harms”;

• The U.S. Food and Drug Administration (FDA) has approved the PSA test for annual screening of prostate cancer in men aged 50 and older. PSA levels between 4 and 10 ng/mL (nanograms per milliliter) are considered to be suspicious and consideration should be given to confirming the abnormal PSA with a repeat test. If indicated, prostate biopsy is performed to obtain tissue sample for histopathological analysis;

• In the United Kingdom, the National Health Service (NHS, 2005) does neither mandate nor advise for PSA test, but allows patients to decide based on their doctor's advice.

 

Clinical practice guidelines for prostate cancer screening vary and are controversial due to uncertainty as to whether the benefits of screening ultimately outweigh the associated risks (see above). For those men who opt for surgical therapy (radical prostatectomy) or radiation therapy, it is difficult to interpret the relationship between PSA levels and recurrence/ persistence of prostate cancer after surgical or radiation therapy. PSA levels may continue to decrease for several years after radiation therapy. The likelihood of developing recurrent prostate cancer after curative treatment is correlated to various risk factors, such as the grade of prostate cancer (Gleason score), PSA level prior to treatment, and the stage of disease prior to treatment. Low-risk cancers are the least likely to recur, but they are also the least likely to have required treatment in the first place.

Every year, ritualistically, nearly thirty million men in the U.S. partake in a mass screening PSA test. The current (FDA) guideline is for all men over age fifty to have their PSA checked annually.

 

Of these, approximately 250,000 have a “false positive” result, meaning an elevated PSA level in the absence of cancer. However, to rule out cancer, these men must further undergo excruciatingly painful biopsies that must be repeated every six months for at least the following year if the initial biopsy was negative. It is true that prostate cancer is extremely common in men, more particularly elderly men with 15% of them carrying the diagnosis. However, only 3% of men succumb to the disease. Thus, there is considerable prevalence of non-aggressive prostate cancer (a latent disease that can take a decade or more before reaching a detectable size).

 

The test alone costs the U.S. the sum of $3 billion to which must be added billions more for the biopsies, surgeries and their complications (incontinence, impotence,…), and radiation treatments and their complications. These figures have prompted the test inventor (Dr. Richard Adlin) to publish an op-ed in the New York Times of March 9, 2010 titled: “The Great Prostate Mistake” in which he stated that “The test’s popularity has led to a hugely expensive public health disaster” and further concluded that “The medical community must confront reality and stop the inappropriate use of PSA screening. Doing so would save billions of dollars and rescue millions of men from unnecessary, debilitating treatments”.

 

This is another illustration of population medicine (“one dose fits all”) even though we do not all have the same risk profile given the differences in our biology and environmental exposures. Mass screening disregards individual variability and promotes considerably more unnecessary medical testing and procedures without mentioning the emotional toll it takes on patients and their families. Further, since the test is not recommended, can be accompanied by harmful effects which do not outweigh its benefits, may result in over-diagnosis and over-treatment, involves risks of treatment complications, and alone costs the nation $ 3 billion/year, is it not advisable to forego it and reserve it solely to individual patients on their doctors' advice?