Important end-points missing

Clinically Trials Missing Important End Points and Side Effects

The donut hole

The donut hole: Over and over again in journal articles I find missing issues that a medical scientist would include in a clinical trial, but not marketing scientists. The reasonable conclusion is their absence (the donut hole) is to avoid unfavorable results. Too often if included the drug and patient and physicians made aware of the major side effects, the drug would not be a blockbuster. An on point example is the selective COX-2 inhibitors, Vioxx and Celebrex which when taken long term among the elder triple the risk of heart attack. (There are numerous articles exposing how these drugs have caused over 100,000 deaths and over 250,000 heart attacks and strokes. Short-term studies didn’t prove the risk. Serious side effects are bad for business. Below is a study which doesn’t list side effects, though has very low compliance for post MI medications that lower blood pressure, cholesterol, and prevent blood clots. The issue of side effects was ignored.

A common second way is to include the major endpoints with minor ones, and published the results in one figure. Recently I fell for this and posted a treatment as worth taking, when I read the British Medical Journal article for the second time and spotted that angina pain was included with deaths and heart attacks, I had to edit the articles on cardiac disease, and took down the study. Pharma knows that their opinion leaders use the journal article abstract, and 90% of physicians who read an article, just read the abstract. Or for the 10% who read the article, most wont spot the deception of the composite outcome buried in the 10 pages of details. Abstracts and article conclusions are key ways that pharma promote their products.

Pharma writes and edits clinical trials for journal articles so that their role is denied. Rarely does their come to the surface. Thus there are statements sprinkled throughout the article that promote this deception. See Ben Goldacre’s Bad Pharma, chapter 4, where he develops the role of pharma in clinical trials and the writing of journal articles. Ben also writes that it is common to switch endpoints and objectives from those listed when the clinical trial is registered to what is published in the journal article. Just one of many ways to create positive bias.

Full Coverage for Preventive Medications after Myocardial Infarction

N Engl J Med 2011; 365:2088-2097December 1, 2011DOI: 10.1056/NEJMsa1107913

http://www.nejm.org/doi/full/10.1056/NEJMsa1107913?query=OF#t=articleResults

Pharma’s randomized population studies as the overwhelming norm have donut holes in the endpoints, holes that medical scientist would have filled but marketing scientists don’t. For example in the Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) trial was there were 2 holes: as to side effects, and how did those who dropped out faire with drugs? The study was of those who had an MI and fit the diagnostic code ICD09-CM. They were followed 1 year. It was a study of effect of co-pay upon adherence for those insured by Aetna. Since the goal was NOT to promote drugs, unfavorable results are published. For example prior to the MI (heart attack), 53% had been taking an ACE inhibitor or ARB, 63% a beta blocker (both for high blood pressure), 54% clopidogrel (Plavix), 6% warfarin (both anticoagulants), and 61% statins to lower cholesterol (yet they had an MI). Prior (coexisting) illness congestive heart failure 28%, COPD 16%, diabetes 34%, hypertension 72%, previous MI 16%, stroke 6%. Medication full adherence with modest copay (filling prescriptions at least 80% of the time): 23% for ACE or ARBs, 25% for beta blocker, statins 31%, and all 3 medications 9% (and this doesn’t count those who fill and don’t take the prescription). With zero copay (full coverage) the three classes of drugs hand an increase in prescriptions fill for full adherence of 5.3%, and full compliance incased 3.2% to 12.1% fully complying for all three drugs. And 33% of the patients would not fill any of their prescription (not just once), and it was with zero copay! These stats show a serious breakdown in the public trust of pharma and their physicians. These stats are not out of line with other studies by pharma of how in their view their customers are under medicated.

A medical scientist would have including questionnaire about side effects to be repeatedly filled out by patients in the study. And they would compare the results of those who took no drugs, and some drugs, to those who followed the full regime of medications. The study would be run longer so as to uncover those that take years to become statistically relevant, such as cancer, psychiatric conditions, and osteoporosis. And he would follow the use of anticoagulants, arrhythmia drugs, other hypertension drugs, and anxiety medications (downers), which are drugs normally given following an MI. Beta blockers and ACE inhibitors have major psychiatric side effects. “Beta blockers interfere with the binding to the receptor of epinephrine and other stress hormones [neurotransmitters], and weaken the effects of stress hormones” Wiki. Calcium channel blockers and statins both have serious psychiatric side effects. One question to tease out would be how those following an MI who taken pharma’s drug cornucopia faire compared to those who don’t?

Lacking the raw data, the possibility of manipulations to favor drug outcomes are like, for it is the norm. This issue would exist if research was run by medical scientists instead of marketing scientists. Moreover spin is the norm in the conclusion section of journal articles, and this one is no exception. The lack of correlation for those who took their drugs as prescribed to improved outcome, though mentioned in the article, was attributed the lack of efficacy of the drugs. However this was left out of the conclusion and used for full compliance the % of those who filled the prescription at least once rather than the 80% group, thus hiding the shocking low compliance.

The low compliance is supported for statins (31%), is made even more so for the elderly, since their ATP production has declined to a clinically important level. Statins block ATP production by lowering the essential Q10 40%. Quality of life clearly deteriorates for the elderly: a large Canadian study had 75% dropout by 2 years, and 80% in a NJ study, and their drugs are covered by government medical insurance.

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It sure has become big business: standard treatment following an heart attack (MI) costs $109,000* per year for just for the 3 drugs—none of which are worth the side effects, let alone their price. Remember the marketing department of the drug company are as standard operating procedure manipulating the results to create a positive bias on an average of about 32%, The doctors all have conflicts of interest, and the journal reviewers do not see the raw thus preventing a meaningful peer review of submissions. The claim of significantly better results based on a 2% greater compliance than with those who had a copay, this is deceptive. In other words don’t rely on the results, just consider significant the cost for what, in my father’s day (1953) was cost about $25 a year (he had nitroglycerin as his only medication, and he lived 23 years from his first major MI—nearly killed him. And if you wonder why there is poor compliance (under 50%); the two major reason are a skepticism about the integrity of the pharmaceutical industry and their sales people the primary care givers, and secondly the side effect. That side effects are not even mentioned is one more indication of the marketing department controlling content.

Revascularization is the restoration of the blood circulation of an organ or area, achieved by unblocking obstructed or disrupted blood vessels or by surgically implanting replacements. Though the articles states “no significant difference”, those who took 4-6% less of the drug cocktail had a reduction in end-point event of 7%. I wonder how much better a placebo group would have done. Scientific clinical trials do not justify the drugs, but pharma’s marketing studies do. The Cochrane Review using the better of the studies in their meta-analysis has found that high blood pressure drugs, though they lower blood pressure, they don’t prevent acute events.

Full Coverage for Preventive Medications after Myocardial Infarction

Niteesh K. Choudhry, M.D., Ph.D., Jerry Avorn, M.D., Robert J. Glynn, Sc.D., Ph.D., Elliott M. Antman, M.D., Sebastian Schneeweiss, M.D., Sc.D., Michele Toscano, M.S., Lonny Reisman, M.D., Joaquim Fernandes, M.S., Claire Spettell, Ph.D., Joy L. Lee, M.S., Raisa Levin, M.S., Troyen Brennan, M.D., J.D., M.P.H., and William H. Shrank, M.D., M.S.H.S. for the Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial

N Engl J Med 2011; 365:2088-2097 December 1, 2011 http://www.nejm.org/doi/full/10.1056/NEJMsa1107913?query=OF

Background

Adherence to medications that are prescribed after myocardial infarction is poor. Eliminating out-of-pocket costs may increase adherence and improve outcomes.

Methods

We enrolled patients discharged after myocardial infarction and randomly assigned their insurance-plan sponsors to full prescription coverage (1494 plan sponsors with 2845 patients) or usual prescription coverage (1486 plan sponsors with 3010 patients) for all statins [lowers cholesterol], beta-blockers, angiotensin-converting–enzyme inhibitors, or angiotensin-receptor blockers [blood pressure meds]. The primary outcome was the first major vascular event or revascularization. Secondary outcomes were rates of medication adherence, total major vascular events or revascularization, the first major vascular event, and health expenditures.

Results

Rates of adherence ranged from 35.9 to 49.0% in the usual-coverage group and were 4 to 6 percentage points higher in the full-coverage group (P<0.001 for all comparisons). There was no significant between-group difference in the primary outcome (17.6 per 100 person-years in the full-coverage group vs. 18.8 in the usual-coverage group; hazard ratio, 0.93; 95% confidence interval [CI], 0.82 to 1.04; P=0.21). The rates of total major vascular events or revascularization were significantly reduced in the full-coverage group (21.5 vs. 23.3; hazard ratio, 0.89; 95% CI, 0.90 to 0.99; P=0.03), as was the rate of the first major vascular event (11.0 vs. 12.8; hazard ratio, 0.86; 95% CI, 0.74 to 0.99; P=0.03).* The elimination of copayments did not increase total spending ($66,008 for the full-coverage group and $71,778*** for the usual-coverage group; relative spending, 0.89; 95% CI, 0.50 to 1.56; P=0.68). Patient costs were reduced for drugs and other services (relative spending, 0.74; 95% CI, 0.68 to 0.80; P<0.001).

Conclusions

The elimination of copayments for drugs prescribed after myocardial infarction did not significantly reduce rates of the trial's primary outcome. Enhanced prescription coverage improved medication adherence and rates of first major vascular events and decreased patient spending without increasing overall health costs. (Funded by Aetna and the Commonwealth Fund; MI FREEE ClinicalTrials.gov number, NCT00566774.)

Supported by unrestricted research grants from Aetna and the Commonwealth Fund to Brigham and Women's Hospital.

Dr. Choudhry reports receiving consulting fees from Mercer Health and Benefits and grant support from CVS Caremark; Dr. Glynn, receiving consulting and lecture fees from Merck and grant support from AstraZeneca and Novartis; Dr. Schneeweiss, receiving consulting fees from WHISCON and grant support from Pfizer and Novartis; Ms. Toscano, Dr. Reisman, Mr. Fernandes, and Dr. Spettell, being employees of and having an equity interest in Aetna; Dr. Brennan, being an employee of, having an equity interest in, and receiving board membership fees from CVS Caremark; and Dr. Shrank, receiving consulting fees from United Healthcare and grant support from CVS Caremark and Express Scripts.