Tuesday, August 30, 2005

ADA statement- metabolic syndrome not a useful concept any longer

In what will be to many a surprising comment,The American Diabetes Association issued a statement challenging the value of the metabolic syndrome label. Their chief scientific and medical officer was quoted in USA-Today as saying "We don't believe there 's a syndrome"
The ADA is quoted as saying that each of the conditions that make up the syndrome are potentially life threatening but there is no evidence to suggest that someone with multiple factors is any sicker . Headlines aside, the ADA position is put forth in an ADA Statement published in Diabetes Care 28:2289-2304, 2005. It is a length and scholarly review of the subject and is worth plowing through because this clustering of cardiovascular disease (CVD) risk factors has reached "disease equivalent" status replete with a ICD-9 code and has become part of the medical vocabulary of patients as well as physicians. Here are some of the key points of the statement.
Although certain CVD risk factors are prone to cluster, there is considerable doubt as to the predictive value of the syndrome, i.e. does the syndrome impart any risk greater than its individual components.
In regard to whether metabolic syndrome is a coronary risk equivalent, the authors quote a study by Wilson et. al. which showed that when an elevated blood sugar is taken out of the definition, the 10 yr. Framingham risk does not reach the ATP III's threshold for risk
equivalent. So using the NCEP definition of Metabolic Syndrome, it matters which of the 3 out 5 criteria are present as data suggest that all combination of factors leading to the syndrome diagnosis do not convey equal risk.
There is considerable uncertainty regarding the syndrome's pathogenesis, i.e.everyone with the label-and there are various definitions proposed-may not have the putative underlying mechanism which is thought to be insulin resistance.
In short, the syndrome lacks a precise definition, is of doubtful value as a CVD marker and its underlying pathophysiology is dubious.
The ADA therefore recommends for physicians to treated all CVD risk factors per se and not label patients with the term metabolic syndrome because that may give the impression that the syndrome denotes a greater risk than its components which is a conclusion for which the evidence is not convincing. The term has been a useful paradigm to the extent that atttention was drawn to the fact that some CVD risk factors cluster in patients so predisposed and doctors need to evaluate a patient who has one major CVD risk factor for other risk factors.
The statement is likely to have wide impact as ADA is well respected and their European cohorts (European Association for the study of Diabetes) published the same statment in the journal Diabetologia.
One of the news reports mentioned the term "disease mongering" referring to drug companies' promotion of the syndrome to develop markets for its treatment. This is a concept that has received considerable interest in Australia and in the pages of the BMJ and that deserves a posting of its own at a later date.

Friday, August 26, 2005

A follow up to restless leg syndrome post and comments

Medscape has an article explaining new warnings issued by the FDA on Requip.RebelDoctor Weblog had commented on my earlier blog indicating that he too felt RLS was probably under-diagnosed and mentioned his approach to therapy . Unfortunately, I had to delete the comments for that blog- including his- as my site was bombarded with spam-comments. (I also put up the usual anti-spam- comments protections.) I did not want the good Doctor from Mississippi to think that I did not appreciate his comments.
Medscape indicates the reason for the new warnings on Requip relate to the sudden
"falling asleep" apparently without warnings that have been reported in patients taking Requip. Physicians in Canada had been alerted to this issue as early as 2000. (for some reason I have been unable to get back to Medscape to set up a link). The major issue, here, is should patients on that medication be driving. The PDR section on Requip indicates that patients should not drive until they determine that the drug does not cause drowsiness and if they do experience drowsiness doing everyday activities they should not drive.

Homeopathy-Lancet article critical-NHS pays for it

A recent article in Lancet appropriately criticizes homeopathy and concludes there is no scientific basis for it and it does not work. This is no surprise. It is surprising that the NHS pays for it and the Lancet article ( registration required) quotes a WHO draft report supporting homeopathy claiming there is valid evidence of its efficacy. For some reason I would expect better from WHO.

Wednesday, August 24, 2005

Restless leg syndrome-unrecognized epidemic or drug company hype

This sounds a lot like my recent posting on bipo*r disease and allegation of physician underdiagnosis and it should since it is another example of the same issue.
This time we look at an article in a recent Archives of Internal medicine and a reporting of that article in Internal Medicine World Report ( August 2005).16,00 patients were given questionnaires re:RLS. Weekly symptoms were reported by 773 patients ( 5 % of the 15, 391 patients who completed the questionnaires.) Apparently 337 reported discussing their symptoms with their physician but only 21 had received a diagnosis of RLS.
Realizing full well that the plural of anecdote is not data, I still have a urge to relate my experience in seeing patients in an internal medicine practice for over 35 years. No patient had a complaint that could be referable to RLS diagnosis ( not to say they didn't have it , they just didn't complain of it) and only two gave me the history of that disorder having been diagnosed elsewhere and were on treatment. One of the two gave me a web site to learn about the disorder. A 3/4 page ad is found in the same issue of Internal Medicine World report informing the reader about the "first and only FDA-approved treatment for moderate to severe Primary RLS", namely ropinirole- trade name Requip which is a dopamine agonist.FDA gave approval in May 2005. The manufacturer of ropinirole is listed as a source of funding for the study; its name is not mentioned in the article. To the extent that patients complain of RLS symptoms and are not counseled about it and perhaps offered the option of medication and have their serum iron levels measured, the physicians are not doing their job.(articles and lectures on RLS-locally there have been a number of "free" dinner lectures on RLS by a local movement disorder specialist-seem to not emphasize in their mentioning of the association of RLS and low iron that at least post menopausal women and all men should be evaluated for GI bleeding if the iron is
low.)
Maybe there is an almost epidemic of RLS and maybe docs are fairly clueless about the whole thing, but in light of the events of the last few years regarding revelations about drug company manipulation of the medical informational process, you just have to be a little skeptical.
On a possibly related note, there seems to be a flurry of recent publications-typically from the medical education companies-about the putative mechanistic reason(s) behind the reported increased prevalence of macrolide resistance and the apparent theoretical advantage of a new antibiotic class-the ketolides- in that regard.

Monday, August 22, 2005

Canadian Supreme Court ruling,CMA recent vote-is private care on the way in Canada?

Delegates at the Canadian Medical Association 's recent meeting voted to not reject the alternative of private care in Canada if waiting times are prohibitive. A recent CBC article describes various medical services already in Canada that seem more private than public including employer based health insurance that may provide ammenities outside of the benefits covered by the provencial plans. Canadians who can afford it sometimes also vote for private care. They vote when they buy insurance that will help pay for surgeries south of the border if the wait is too long. Many Canadian physicians also voted already when they left home and moved to the U.S. to practice pirvate medicine.

Friday, August 19, 2005

Dueling medical mathematical models- to choose- An act of faith?

The August 16, 2005 issue of the Annals of Internal Medicine published an article by Dr. David M. E. Eddy et al using a mathematical model called the Archimedes model. This computer based model was applied to the question of is it more cost effective to give metformin or to employ the methods of the Diabetes Prevention program (DPP) of lifestyle modification to prevent or delay the onset of diabetes in high-risk individuals. The DPP had shown that over the almost three years of the trial there was a relative risk reduction of 58% from life-style and 31% for metformin. An earlier article in the same journal used a different model (Markow model) to attempt to answer the same question. The authors concluded that the lifestyle modification was more cost effective. The Eddy article found the opposite to be the case. The views of two editorialists were sought and published in the August Annals issue in an apparent attempt to place things in context.
One editorial author was Dr. Michael M. Engelgau who was one of the researchers in earlier study that found lifestyle modifications more cost effective. Not surprisingly he criticizes the Eddy model saying in part " I believe Eddy and colleagues' criticisms [of his model] are based on inaccurate descriptions of the DPPRG model". Eddy et al in their introduction state their method is " more thorough,clinically realistic and independently validated".
So whose model is better? Whose conclusion is correct? Is there a "correct"? Dueling experts with opposing conclusions.
The Archimedes model also found that it would be more cost effective to wait until a person developed diabetes before instituting either metformin or lifestyle modification. It will be interesting to see what the folks at the America Diabetes Association or Joslin Clinic say about that.
In real life, of course, a physician will attempt to convince the "pre-diabetic" to loose weight and exercise and may even in addition suggest metformin. But these models are less used to aid individuals docs and individual patients decide what to do that they are to make policy decisions for large organizations in regard to how to allocate funds.
The line between "pre diabetes" and diabetes is arbitrary and the definitions of these two conditions change with the edicts of the ADA and the physiological processes that Eddy claims to model with differential equations are poorly understood and always in flux as new biological insight are gleaned. The output of these models is quality-adjusted life-years (QALY) in which researchers claim to be able to measure and average the "quality" of a person's life. I have posted before on the topic of QALY and cost effectiveness articles.
These models have assumptions on top of assumptions, offer little transparency, are essentially mysterious black boxes to all but a few of the researchers who are expert in such matters and for physicians , or for that matter, policy makers to accept these at face value ( and here how can you when two studies are so contradictory?) requires faith.

"Addicted" to sun bathing ? Arch. Dermatology article

A recent study published in the Archives of Dermatology investigated the use of the CAGE-alcohol abuse screening too, somewhat modified- and another similar tool in beachgoers on a Texas beach. The authors reported that 26% of participants could be classified as having a "substance-related disorder" on the basis of the CAGE screening tool and 53% using the modified DSM-IV-R diagnostic criteria
Some skeptics might say that this is really a stretch and one more example of a hypertrophied tendency to medicalize every human behavior and trait and a rampant nanny-ism wherein we must figure out a way to stop everyone from doing anything that might be considered foolish, unhealthy or contrary to what the nagging nannies would have us do or not do.
The Archives article suggested that the recognition of tanning as substance-related disorder opens the door to possible new techniques to curb the practice, particularly in regard to tanning salons and the legal prohibition of children using them. They say outdoor UV exposure control might be more problematic ( Ya think).
Hello, I'm Kevin, I'm a u-v light exposure holic. Hello Kevin. (And another thing is U-V light exposure a substance?

Monday, August 15, 2005

Bipol*r disease, unrecognized epidemic or drug company hype

Several months ago at a local internist's club meeting we had a presentation by a psychiatrist about bipolar disorder. He is a co-director of a mood disorder program at a local medical school. (yes, it was sponsored by a pharmaceutical company)The take home messages appeared to be, it is far more common than generally recognized, suspect it if a young person is "depressed" or has a history of depression as a teenager, or has ' racing thoughts" and some of these newer atypical antipsychotic drugs are useful.In 35 plus years of practice, in one form or another, I have probably been aware of less than 10 patients with manic-depressive disorder.The other five internists at my table expressed a similar experience. I do realize that these patients can be very difficult to manage and may impose considerable burden on their family and friends. Typically,internists do not come home at the end of the day saying "another day, another 4 bipolars in the office". Ads from a major drug company (Astr*Zen**ca) tell us that 49% of people with bipolar disorder are undiagnosed and send the reader to a web site for a "validated screener" This screen is 13 questions ending with "have you ever been told you have bipolar disease?" It is said to be based on a paper by PM Hirschfield in Am. J. Psy 2000: 157 (11) 1873- 1875).That web site then can send you to a dosing schedule for an atypical antipsychotic manufactured by that drug company.I cannot imagine an internist or FP doctor taking on the assignment of treating a bipolar patient with a relatively new drug which it is very likely that he has only recently heard of. At the meeting re bipolar, a number of the internists were surprised to learn that if a patient with bipolar disorder is clinically depressed that the treatment is not an antidepressant but a mood stablizer. This might give you some hint as to the general level of expertise an internist has in this area.
But I cannot but wonder that if we see a obviously depressed patient in the office maybe we should use that or some other screen for bipolar and if there is any hint of it on the answers get the patient off to a psychiatrist rather than reaching for the SSRI prescription.
If any psychiatric bloggers out there could offer a puzzled internist some thoughts on this I would appreciate it.

Friday, August 12, 2005

IM and EM residents and EKG reading-overall competency score is low-AJM article

A disconcerting article appeared in the August 2005 issue of the American Journal Of Medicine.
87 internal medicine residents and 33 emergency medicine residents were given 12 test ekgs to read. The residents were from two institutions and all residents were exposed to formal training in EKG reading. Unfortunately the manner in which the results are displayed is a bit confusing, it uses a"proficiency score",which to me obscures more information than it illuminates, but the bottom line is that neither group did very well. One table shows that of all the residents (IM and EM in one grouping) only 40% had the correct answer for an acute MI.(52% had a partially correct answer-what ever that is and only 8 percent had it wrong, apparently they gave partial credit.) So it is hard to figure out how many could or could not recognize an acute MI. But the authors, who we assume did understand the data, concluded the overall competency score was low. Further,they reported that their results were similar to several other studies that evaluated EKG reading skills in house staff.
I find it amazing that any number of IM residents greater than zero were unable to diagnose a typical acute MI or V. Tach. In medical school, our senior year we had a course in EKG interpretation and we all purchased a small text by Dr.George Burch on that subject. As IM residents we were conversant in the details of the proposed minutiae of the differential diagnoses of V. Tach. vrs supraventricular tachycardia with aberration.Interestingly, we had no formal courses on EKG interpretation as residents. Further,The chief of surgery made sure that his residents could recognize the EKG patterns of acute MI as he walked the walk of his theme that surgeons were physicians who knew how to operate.
I am reminded of a blog reference to an article in which it was noted that of 259 IM residents who were tested regarding ventilator use, about half did not know how to set the tidal volume in an ARDS patient. I also recall an Annals of Internal Medicine article which-although it emphasized other aspects of the story-revealed the apparent ignorance of house staff in realizing the importance of evaluating a upper lobe infiltrate in an alcoholic with weight loss and cough for TB.
I realize these are limited, possibly biased samples and from them it may be not appropriate to hypothesize a trend that suggests woefully inadequate training in internal medicine. I really do not want to believe that. I read about an IM program that is now two years post internship rather than three. I read that ACGME has devised requirements that necessitate more being crammed into this shorter time frame. Residents must now learn "system based practice" and quality improvement projects may be required and the time they can spend in the hospitals is restricted and , yes, there is simply more medical knowledge out there to learn.
I know that older professionals in many fields seem to always think the newer generations cannot live up to the standards that the old guard set, that the new kids have it easier, are soft and do not know as much. I'm sure I am guilty of that mind set, but-my goodness-an internist has to know how to read a EKG and if I were an EM resident knowing I would see chest pain patients every day, I would make sure I could recognize an acute MI ekg pattern and not wait to have a lecture on the topic to become proficient. I hope that this article does not accurately reflect the ekg interpretation skills of residents in IM and EM.
And another thing, sometimes I think that physicians believe that reference to evidence based medicine must always be made even if the application seems gratuitous. The authors of the article say in the purpose section " yet there are no evidence based guidelines for assessing [ekg reading] competency". How about just giving them ekgs and seeing if they can interpret them? We really don't need and will never have EBM guidelines for everything.

Wednesday, August 10, 2005

Practice guidelines in patients with multiple diseases not just inappropriate -may be harmful-JAMA article and editorial

That single disease guidelines may be harmful in multi-disease patients is a topic I have talked about before. Dr. Mary Tinetti published an excellent article on that topic in the NEJM in 2004.
An important and hopefully influential article on this same general issue was published in the August 10, 2005 issue of JAMA by Dr. Cynthia Boyd and colleagues. Their bottom line,take home message is The use of practice guidelines as the basis for pay-for-performance initiatives that focus on single disease treatments are not suited for patients with multiple diseases may well be harmful and this particularly impacts the elderly. Current single disease guidelines as applied to multi-disease patients are not ready for prime time and because of their naive simplicity will never be.
I would put it this way : The fact that a given treatment for a given disease in a certain selected study population is demonstrated to be efficacious and safe is not sufficient reason to apply that treatment to a given patient with co-existing other diseases. It follows that a physician should not be subject to economic sanctions on the basis of adherence to single disease practice guidelines in a patient with multiple comorbidities.
The editorialist, Dr. Patrick J. O'Conner,makes recommendations for guidelines that clearly imply guidelines as they currently exist are not adequate. He says, " Strategies to address the limitations of current CPG's (clinical practice guidelines) need to be developed and implemented,including providing recommendations based on level of evidence for particular patient groups and considering the potential economic and personal burden on the patient and caregiver as well as potential interactions with comorbid conditions".
Representatives of organized medicine who will meet with and negotiate with representatives of big insurance and Medicare have a very strong argument to make. As Dr. Dr. Boyd et. al. said:
the guidelines are not designed for quality assessment,they are recommendations based on varying levels of evidence by committees largely dominated by specialty groups for the management of single diseases, their application could lead to " perverse" economic incentives to emphasize the wrong aspects of care and the guidelines assume that clinical judgment and patient preferences will be incorporated into clinical decisions and yet when these guidelines are applied for quality grading no allowance is made for clinical judgement or patient preference. To apply single disease guidelines to patients with multiple diseases should not be negotiable.
The arguments of Dr. Boyd et al and Dr. O'Conner are cogent, important and should be acted on by resisting on whatever fronts present themselves any pay-for-performance schemes which ignore the complexity of human illnesses and desires and circumstance and judge clinical quality by adherence to simplistic single disease management rules and guidelines which themselves may be limited by the often flawed evidence underlying them.
As much as I agree with the arguments of the two articles, I am troubled by the assumption that both authors seem to make, namely that pay-for-performance is inevitable. I am reminded of the flurry of articles in the early years of the "gate-keeping" fallacy that it will occur, it is occurring and you doctors out there better get on the bandwagon or be left out. There was no shortage of players in medical academia who-for whatever motivations and some may have been well intended-who were complicit with the insurance industry. Pay-for performance may be one of those things that we would be better off being left out.

Tuesday, August 09, 2005

AMA News: Docs urged to detect RX drug abuse

The war on drugs continues.New theaters of operation are always opening up even though the enemy in older venues of combat have not been defeated.Emphasis is currently on the amphetamine issue and more recently CASA ( Center on Addiction and Substance Abuse) targeted prescription drug abuse, said by them to involve 15.1 million Americans in 2003.Since this is an activity that the perpetrators strive to keep secret and admittedly use all manner of lying, cheating and subtifuge to evade detection one cannot help but question the accuracy of this number particularly when done by an agency who has no interest in underestimating the number. This number appears, however, without editorial critique, in the August 8, 2005 issue of AMA News (no link given as this publication is now open to AMA members only). For some reason I cannot hear the term "drug abuse" without thinking of someone hitting a capsule with a hammer or shouting at a pill saying "you dumb SOB, you made me nauseated".I mention this CASA news article only to highlight a recent rant by DB's Medical Rants on the drug war.I agree with his comments completely.
William F. Buckley Jr., of National Review fame,lead a symposium in July 1996 which concluded that the war on drugs had failed. Thomas Szasz in that symposium said that Dr. William Bennett-former drug czar(It was never explained why a government official in the U.S. would be referred to as a czar)-was right when he said that drug use and drug controls were primarily moral issues. Bennett saw self medication as wicked and criminalization of that behavior as virtuous while Szasz saw self medication as a basic right and drug use criminalization as hypocritical and unenforceable.Everyone will not agree with Szasz's libertarian views but Buckley is no libertarian. You do not have to agree with Szasz's views on what he describes as the "myth of mental illness" to appreciate his thoughts on the drug war.
Decades earlier Dr. Milton Friedman said that the deleterious effects of the drug war would be the same or worse that those noted in the Prohibition, which finally got so bad the law was repealed.
The AMA news article was replete with suggestions for doctors to better detect Rx drug abuse such as calling the patient's old doctor, asking the patient if he has a history of drug abuse ( that should work) and medical educators were admonished to do a better job teaching medical students how to detect such behavior.

Monday, August 08, 2005

NEJM editorial: Modafinil about as good as coffee

The August 4, 2005 issue of the NEJM has an interesting article on the new "alertness" drug, modafinil, and an editorial that expressed skepticism about its value.
5-10% of shift workers exhibit daytime sleepiness and on shift drowsiness to a significantly greater degree than most other workers.That sub group is the current target for the proposed use of modafinil which would hopefully improve the quality of life for these folks and increase productivity as well as perhaps have a favorable effect regarding safety issues.If the disturbance are deemed severe enough the diagnosis of shift-work sleep disorder is made replete with an ICD code. ( Since this has become a codable disease,one wonders if an employer firing a worker for being too sleepy at work would be at risk for an EEOC action.)
The authors conclude that modafinil is "of some value in the clinical management of sleepiness associated with shift-work disorder".It has been approved by the FDA for the treatment of excessive sleepiness associated with shift-work sleep disorder.The editorialist, Dr. Robert C. Basner,quotes a 2002 published comparison with caffeine saying that improvements in performance and vigilance with modafinil were similar to 600 mg of caffeine. For reference,a Pepsi has 55 mg of caffeine,Red Bull, 80 and drip coffee, 110-175.Max strength No Dose is a 200 mg caffeine tablet.
So the results from modafinil are less than spectacular.
Perhaps more interesting were the comments made by the authors that data was fully accessible to all of the authors and the sponsor(in this case the manufacturer of modafinil) placed no limits on the interpretation or publication of the data.This type of reassurance will likely become part of the boilerplate of medical articles.This hopefully represents more evidence that there is a bit of meaningful push-back to the alarming role that some drug manufacturers have had in the control and manipulation of data from clinical trials. Certaintly there is much more awareness of that possibility now and journal editors and journal readers look at drug trials in different way.

Thursday, August 04, 2005

Skepticism about ACP's initiative in Quality and P4P

Dr. Philip R. Alper,Fellow at the Hoover Institution,in a recent column in Internal Medicine World Report expresses concerns about ACP's recent efforts to- in their own words- "quickly engage[ed]to ensure that the interests of internists are represented in this national issue" The issue is the intersection of quality of care and pay-for-performance.Visible evidence of this adroit move is the "partnering" of ACP with AAFP,and AHRQ(Agency for Healthcare Research and Quality) and America's Health Insurance Plans.This union of collaborators is called AQA ( Ambulatory Health Quality Alliance). Let me quote and paraphase some of Alper's concerns.
The AQA announced a "starter" set of 26 clinical performance measures.Dr.Alper wonders if the starter set is 26, how many will we finally have to deal with. Evidence changes constantly and therefore the measures would have to be in constant flux but there is always a lag-sometimes a long lag-between changes in evidence and re-adjustments of guidelines.He says "few if any authoritative advisory systems can be trusted without question, let alone applied blindly to individual patients." He asserts that "the real driver behind the quality movments are the payers." Thus, only as much quality as Medicare or private insurers are willing to pay for will get done-unless of course it is to come out of the doctor's pocket". These two sentences are what it is all about.ACP will function to supply the veneer of concern for patient care to the process and will become an even more powerful controller of who gets to be and to continue to be an internist.
Dr. Alper is also skeptical of ACP motives."...the eagerness of the ACP to seek a place at the quality table may do more good for the ACP that for its members of their patients". He says we already have clinical quidelines to spare "But knowing how to keep performance measure implementation from turning physicians into compliers rather than thinkers and robbing us all of the ability to recognize a sick patient remains to be determined".
Alper asserts that the power base of ACP is in large institutions while most internists are scattered in small practices and that ACP has made a business of medical education and maintenance of standards. Whose interests will ACP represent as they swim with the sharks of the insurance industry?

Wednesday, August 03, 2005

New report on NHS speaks poorly for the single payer system

A recent lengthy report on the British NHS is a good source of ammunition for those who believe that a single payer system for health care is not the way to go. If you live in Wales private insurance may be the way to go if you can afford it as 36 % of patients have a six month wait for an operation. Wales also seems a poor choice of place to have a heart attack as the report indicates no hospital in Wales administered the thrombolytic agent within the hour time guidelines suggest.The report documents considerable regional variation in health quality indicators indicating that single payer system are not immune to this phenomenon of variation which has received much criticism this side of the Atlantic.

When hypertension mega-trials disagree-what do you do?

The topic of conflicting results from BP treatment trials was considered in a roundtable discussion in the July 2005 issue of The Journal of Clinical Hypertension by Drs.Thomas Giles,Marvin Moser and Suzanne Oparil.The JCH is on line but not all articles are available including this one. Here are some of the highlights and my thoughts.The starting point is the assertion that there are major differences between the outcome of ALLHAT, the second Australian National BP Study (ANBP2),and ASCOT. Giles said they all actually show the same thing,namely lowering BP is a good thing and the benefits derive from the BP lowering per se. This is not to say phenotypic differences may not be important.There were apparent phenotypic differences evident in ALLHAT. 36% of the 42,000 participants(when we say mega trial for ALLHAT we really mean MEGA)were African Americans and in that group the diuretic was better in regard to stroke and heart falure than was an ACE inhibitor. Dr. Oparil said that in ALLHAT African Americans from the southeastern United states were "over-sampled" and many of that group had higher BMIs (the average was almost 30).In ANBP2,an ACE inhibitor seemed better and the participants were mostly white.So the population from which these two trial recruited participants was clearly different and that could explain some of the apparent differences in outcomes.These trials are context dependent,ie. which drugs,which dose of the drugs, which combination(often the combination and the sequencing of additions of drugs seems contrived and not realistic) to which group of patients for how long.It should also be remembered that with large numbers, small difference in outcomes become statitstically - but not necessarily clinically -significant and when multiple subgroups are analyzed statistically significant differences always are found. Another issue is are the drugs always compared fairly.
For example, in ASCOT the beta-blocker (atenolol) was begun at a 50 mg per day dose, which -according to Dr. Giles- is not an adequate dose. Dr. Oparil pointed out that another issue is the duration of the trials ( often 3- 4.5 years) may not allow adequate time to discern the longer term metabolic effects e.g. diuretics and glucose intolerance risks.
The bottom lines may be: 1)the lowering of BP may be more important that the particular drugs used (with the proviso that in certain groups of patients a particular class of drugs may be important to use as in ACE inhibitors in diabetics)
2.Mega-trials are complex both in design, interpretation and in selection of participants.The devils really are in the details and overblown pretentious "final" conclusions re choice of BP medications made today and codified in guidelines may well seem naive and silly to future students of Blood Pressure.
Some- but not all- patients with HBP are salt sensitive which might serve to remind us that maybe we should take over-emphasized conclusions taken to be universally true with a grain of salt.