GLG News by Forrest Rubenstein, MD

Implications:  Bariatric surgery is a major operative procedure that caries significant morbidity and mortality risks due to the comorbid diseases seen in this patient population.  This procedure is increasing in frequency as more patients are willing to have it and more surgeons are becoming proficient. The mortality rate is ~ 1 % at 1 year and 6% at 5 years which is greater than the population at large.

Analysis:  The URL for this article is:

http://www.medscape.com/viewarticle/567726?src=mp

http://www.medscape.com/medline/abstract/17938303 

There is an excess of cardiovascular deaths and suicides in patients following bariatric surgery. 

These patients require careful pre-op evaluation (ie cardiac) and optimization and careful post - op monitoring to decrease some of the preventable deaths (ie suicides).

This requires a team approach as the risks to these patients does not end after the perioperative period.

Meticulous attention to surgical detail, patient selection for the individual procedure (bypass vs lap band, open vs laparoscopic, etc), perioperative glycemic and BP control, PE prophylaxis, and dietary and emotional counseling are all important components of this procedure.

Implications: This article presents the new CMS guidelines that deny higher payments for the additional costs associated with treating patients for certain hospital - acquired infections and medical errors. While these are laudable goals, to assume that all infections are the result of poor medical practice is an oversimplification. The development of nosocomial infections also has to do with the patients disease processes such as diabetes, morbid obesity, immunosuppression, tobacco abuse, etc. While few physicians would argue against enforcing these rules for documented mistakes (medication errors, transfusion mistakes, and objects left in patients bodies), most recognize there is a certain baseline of these other infections which cannot be avoided. Hospitals should only be penalized when their risk adjusted incidence exceeds a standardized baseline.

Analysis:  

Once again CMS takes a good idea and turns it into punishment in order to save money rather than using this initiative to improve patient care.

Stating that all line infections or all mediastinitis is preventable is foolish as well as ignorant. This will make patients and administrators think any of these outcomes equates to poor medical practice. In fact they just as often reflect the higher acuity of patient illness that requires more invasive therapy. Obviously, institutions with high numbers of these adverse outcomes are suspect and should be investigated.

A better approach would be to reward those institutions performing at an exemplary level and only penalize those which are substandard. These exemplary institutions could highlight the changes they made to improve outcomes to the benefit of patients everywhere.

Institutions are likely going to limit services to high risk patients rather than risk a huge financial penalty for trying to provide them with the best care available.

Implications:    Several large drugstores are establishing retail medical clinics within their stores much as eyeglass stores have had optomitrists on site.  There is no problem with these clinics per se as long as they practice within the scope of the practitioners license and skill.  There are concerns that those clinics staffed by non physicians will be practicing inferior medicine beyond the scope of the practitioner.  As these clinics become more widespread, they will certainly come under greater scrutiny.

Analysis:  
 These retail clinics could be a good thing for time strapped patients needing a quick fix.

 There are concerns when there is only a nurse or other paramedical provider potentially treating more complex cases than they are trained to handle.

 Even when the clinic is just leased to a physician, the physician must be careful that he is prescribing for the patient's benefit rather than that of the pharmacy.

 The convenience of this setting is appealing but it is no substitute for having a primary care physician who really knows the patient and can help him manage his total health care needs.

Implications:    Zyrtec (cetirizine) is a second generation nonsedating antihistamine that has enjoyed wide popularity.  Zyrtec will become available generically in late 2007 and the generic form is expected to be significantly cheaper.  To virtually extend the patent, the manufacturer is marketing the active enantiomer, levocitirizine (Xyzal) as a replacement for Zyrtec. This required only a fraction of the R&D costs that developing a new drug would entail.  While this could be a boon to the pharmaceutical companies involved in the release, patients have little to benefit from the increased cost.

Analysis:   


 This is only one of the tricks pharmaceutical companies have come up with to prolong their patents without giving patients more for their money.

 This is exactly what happened in 1990 when the "purple pill" Prilosec went off patent. We now have a new "purple pill" esomeprazole (Nexium) which does exactly the same thing for a lot more money. See this link for more info

http://en.wikipedia.org/wiki/Omeprazole   

 
 Another favorite trick is to combine 2 effective medications about to go off patent into 1 tablet to prolong the patent at a much greater cost than the 2 medications individually.


 Xyzal (levocetirizine) is the active R-enantiomer of cetirizine (Zyrtec). The present formulation also contains the inactice enantiomer in equal proportions. This is not truely a new drug and is expected to be no more effective than Zyrtec and much more expensive.

Implications:    Cordis introduced the FIRE STAR™ Rx PTCA Dilatation Catheter to the European market.  This catheter reportedly has a lower profile than other devices on the market which enables it to cross highly stenotic or tortuous lesions.  There are no controlled studies showing device this offers any significant advantage for most angioplasty procedures.  The Fire Star device will likely become a part of the armamentarium of interventionalists but will not be the workhorse catheter unless a true outcome advantage can be demonstrated or the price is competitive with the devices currently available.

Analysis:  
The URL for this article is:

http://www.medicalnewstoday.com/articles/76866.php 


 While this device may be helpful in difficult situations, most angioplasties will not require this advantage.

 If priced the similar to other devices on the market, it may take market share. If more expensive, it will only be used when the other devices fail to cross.

 Either way, it is unlikely to significantly impact Cordis's economic situation.

Implications:    Type II diabetes and the metabolic syndrome are highly correlated with obesity. These diseases are epidemic in our society.  Weight loss has been definitively shown to reduce morbidity and mortality in these patients with complications from their obesity.  Bariatric surgery is a highly effective strategy for treating morbid obesity. It reliably produces greater weight loss than any other treatment.   As these procedures do have risks and potential complications, they should be considered a part of the treatment plan along with diet, exercise, and risk factor reduction.  No single strategy is best for all patients so this therapy needs to be individualized.

Analysis:  
 Bariatric surgery has been proven to induce greater weight loss than any other treatment.

 There are several different surgical procedures ( restrictive, malabsorptive, and combination) with different indications and different complications.

Type II diabetes is highly correlated with obesity and weight loss has been shown to improve glucose metabolism.

 Only overweight diabetic patients who can be expected to improve with weight loss and those with complications from their diabetes would be expected to have a positive risk/ benefit ratio from this procedure. 

 Medical and psychiatric screening is still an important part of the screening and evaluation process and should not be forgotten.

 Less invasive procedures such as the lap band may be more appropriate for patients who are merely overweight vs those who are morbidly obese.

Implications:    Shire PLC received an approvable letter from the FDA for its nonstimulant treatment for ADHD - Intuniv (guanfacine)   Most of the treatments for ADHD are stimulants (amphetamine derivatives) that can have potentially serious cardiovascular side effects. Unfortunately, to date, no nonstimulant medication has been found to be as effective in controlling the symptoms of ADHD as the stimulants are.   This medication will find a place in the treatment of this very prevalent (and possibly overdiagnosed) disease but its effectiveness for the vast majority of patients has not yet been proven.

Analysis:  
 An approvable letter is a first step in the approval process, but it does not guarantee subsequent approval (as we recently found out with several other promising drugs such as rimonabant).

 While the concept of a nonstimulant treatment for ADHD is very appealing, its utility will only become apparent once it has been prescribed to a broad spectrum of ADHD patients.

 If it is as effective in controlling the symptoms and has a better side effect profile, it could become a blockbuster drug in a short period of time.

 Alternatively, if it is not as effective, it will be relegated to second tier status for those patients who had to discontinue stimulants for side effects or those needing additional medication to adequately control their symptoms.

Implications:    The FDA advisory committee unanimously rejected rimonabant because of concerns of an increase in suicidal ideation seen in patients taking the highest dose of the medication (20 mg). This drug has been proven in several large studies to not only induce greater weight loss than other strategies, but also to improve glycemic control and the metabolic syndrome.  Since these are the major risk factors for cardiovascular disease, this drug was poised to be a blockbuster drug for Sanofi and a huge help for millions of obese Americans with complications from their obesity.  Both Sanofi and the American public will be worse off if this drug does not come to market in the US.  

Analysis:  
 The panel took the wrong approach on this drug. They should not have rejected it outright.

 All medications, all procedures, and in fact every action in life has potential risks and complications. The risk / benefit ratio should be evaluated in each situation.

 If this medication does have an increased risk of suicidal ideation (or even of suicide as many psychotropic medications have), this should be recognized and physicians and patients should be made aware so the patients can be monitored and treated appropriately.

 This risk can be judged in light of the known risks of obesity and metabolic syndrome on cardiovascular disease (the #1 killer of Americans) and the clinical decision could be made by patients and their physician.

 The problem with Vioxx was not so much that it may cause an increase in cardiovascular events but rather that physicians and patients were not adequately informed so they could evaluate the risks / benefits for themselves.

 Research should continue into how to minimize or prevent these risks if they do exist, but more Americans will likely die from lack of this medication than would have committed suicide while taking it.

Implications:    Valsartan (an ARB) and amlodipine (a calcium channel blocker) are both useful drugs in treating hypertension and heart failure.  Most patients require more than 1 medication to reach goal in controlling their blood pressure.  Exforge (a combination of valsartan/amlodipine) will help more patients achieve control than either drug individually.  While this combination may be perfect for some patients, it is unlikely to be a major drug for the company since there is no new advantage for the patients.  

Analysis:   This combination may allow the company to extend their patent on amlodipine, but it does not offer patients anything new.

 There may be some convenience in only having to take 1 pill, but it will probably be more expensive than 2 generic pills and will not be able to be titrated as easily.

 The potential benefits in terms of convenience will probably not justify the increased cost over the soon to be generic equivalents.

Implications:    Peripheral arterial disease is a major problem in this country which is only recently being recognized for the epidemic that it has become.  This problem (PAD) coexists with coronary disease (heart attacks) and cerebrovascular disease (strokes) and has been neglected and underdiagnosed as well as undertreated for years.  Angiogenesis is an exciting adjunct for this disease process, but it is no substitute for risk factor reduction ( weight loss, smoking cessation, exercise and control of hypertension, diabetes, and dyslipidemia) or revascularization.  While this will likely improve the symptoms of some patients with PAD, it has never been shown to improve limb salvage or exercise tolerance as the proven therapies listed above have. To suggest otherwise is irresponsible. Many more years of study may be needed before all the potential problems with this approach become apparent.

Analysis:  
 Angiogenesis is an exciting approach that has been around for several years. It has been studied for coronary disease as well as PAD.

This study of 41 patients is interesting but there is inadequate data to make any clinical decisions. This will need to studied in large trials against current best therapy (revascularization, anticoagulation, and risk factor reduction) rather than against placebo before any scientific conclusions can be drawn. 

Implications:    Retail clinics will see a rapid expansion because of the convenience factor.  Patients want to be seen immediately when they have a health issue.  ER's used to fill this need, but the waits there have become worse than the waits in physician's offices and patients have sought a more convenient alternative.  These clinics will only be appropriate for minor complaints and patients (as well as clinic staff) will realize this in a short period of time.  Inevitably, some patients will make a poor choice and the clinic will be stuck caring for a patient above the capabilities of the clinic and this will tie up the clinic staff and expose them to potential liability.  

Analysis:   
 These clinics may initially relieve some of the stress on the ER's and may take some of the profits from general practitioners, but they will also become victims of their own success - as they are more popular and busier, the waits will increase and the advantages for patients will disappear.

 The lack of continuity of care will plague these clinics as it does the ER - ultimately, patients receive the best care when they see the same physician for their health problems and this physician doesn't have to start from the beginning each visit. Follow-up visits will be necessary, and these will increase the patient's cost of care. 

 The primary care providers who respond to this with defensiveness will lose out. Those who acknowledge it and combat it by providing more convenient, efficient care will actually benefit from this trend.

Implications:    Ximalagatran is comparable to coumadin in stroke prevention.  In this analysis of 7000 patients with atrial fibrillation, the stroke rate was less with ximelagatran than with coumadin with a similar bleeding profile.  The combination of aspirin and coumadin did not improve the stroke rate but it tripled the bleeding complication rate.  Ximelagatran was withdrawn from the market for liver toxicity problems, not for lack of efficacy. It is unlikely to be resurrected for a narrow niche market such as this.  This study is important because it shows the utility of oral direct thrombin inhibitors once one is developed that doesn't cause liver toxicity.

Analysis:  
 The URL for this article is:

 http://www.medscape.com/viewarticle/553506 

 This article is unlikely to have a great impact on Coumadin use.

 It will not impact AstraZeneca's market significantly since ximelagatran was withdrawn for liver toxicity problems, not lack of efficacy.

 This is another study showing the utility of oral direct thrombin inhibitors and will bolster the portfolio of the agent with these properties that does not cause liver toxicity.

 Agents in the pipeline with these properties hold great promise.

Implications: The Medtronic Endeavor III trial has been completed and the results show similar clinical outcomes compared to the Cypher stent in a controlled trial.  While the angiographic endpoints were somewhat worse for Endeavor than Cypher, the MACE rates and revascularization rates were similar.  Endeavor showed a significantly lower rate of MI and MI +death compared to Cypher in this study although these were only secondary endpoints.  Importantly, there was no reported stent thromboses in the Endeavor group.

Analysis:  
 The URL for this article is:

 http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1174924864727&lang=en_US 

 The 2 year follow-up of the Endeavor stent shows slightly worsened angiographic parameters but similar or slightly better clinical parameters and no evidence of stent thromboses.

 This 2nd generation stent should generate interest in Medtronic's stent program and once FDA approved, it should be tried by many physicians who are unhappy with the performance and thromboses seen with the presently available stents.

 The Endeavor stent is presently being tested head to head against both Cypher and Taxus and this trial may change the patterns of DES use in this country.

 Also of interest, the Xience V/ Promus stents will be coming on the market soon and may shake up the DES market even more. Stay tuned......

Implications:
Recent studies have demonstrated higher rates of subacute and late stent thrombosis for DES after discontinuation of Plavix compared to bare metal stents and this calls into question the safety of this trend.

Drug eluting stents account for 90% of stents placed in many institutions in the US and Europe. This is a $5 billion market in the US alone.

The use of DES is supported by studies showing lower restenosis rates, but DES have never been shown to reduce mortality compared to bare metal stents (BMS).

There has never been a study of drug eluting stents (or any stents for that matter) which shows improved long term mortality (5 - 10 years) or quality of life over coronary artery bypass grafting. This needs to be considered in evaluating the best therapy for patients.

This study shows decreased restenosis but no significant survival benefit.

Analysis:  
 The URL for this article is:

 http://content.nejm.org/cgi/content/abstract/355/11/1105

 Also see:

 http://content.nejm.org/cgi/content/abstract/355/11/1093  

 http://www.medicalnewstoday.com/medicalnews.php?newsid=51911 

http://content.nejm.org/cgi/content/extract/355/11/1169 


Stenting has caused a revolutionary change in interventional cardiology and is generally felt to be superior to simple balloon angioplasty.

Conventional wisdom holds that drug eluting stents are better than bare metal stents based on studies showing lower restenosis rates defined by late lumen loss and other surrogate endpoints. No studies have shown a significant improvement in mortality or MACE rates over the long term for these newer devices.

Although the lower incidence of restenosis is a compelling idea, does this translate to improved survival or improved quality of life? - We don't know ! Yet many patients receive this therapy without getting true informed consent regarding the alternatives such as bare metal stents (much cheaper) or CABG (proven to improve mortality and quality of life over the long term for patients with multi vessel and left main disease).

Perhaps we should let science guide our decisions or give patients true informed consent and let them decide - I have never had a patient come to me and ask for the therapy which is best for 6 months or 1 year - they are interested in long term results, so we should be also.

Implications:  
Pulmonary emboli are a major cause of morbidity and mortality in the US - particularly in post-surgical and trauma patients.

The mainstay of treatment and prevention include anticoagulation, sequential compression devices and vena caval filters.

Filters have been the last resort for patients who could not tolerate anticoagulation or who had recurrent pulmonary emboli because they are more invasive and have more potential complications.

The advent of retrievable filters has altered this algorhythm significantly since they can be removed once the risk is over and the long term complications are greatly reduced.

This will markedly increase the use of these devices for prevention of pulmonary emboli.

Analysis:  
 The URL for this article is:

http://salesandmarketingnetwork.com/news_release.php?ID=2017327 

Pulmonary emboli are blood clots that form in the legs or pelvis and travel to the lungs.

They can cause sudden death in otherwise healthy young patients who have had recent surgery or trauma.

Vena caval filters are the most reliable prevention of pulmonary emboli, but their long term use has a greater risk of complications.

Retrievable filters have been available for several years, but it was initially thought they could only be retrieved for up to a few weeks and then had to be left permanently. This inhibited many physicians from using them.

This recent data that they can be retrieved after a much longer dwell time will increase the use of this particular filter as well as the other retrievable filters on the market.

Also see this site for more info on filter retrievals:

http://www.prolibraries.com/sir/?select=error&sessionID=1675 

Implications:  
Anti-oxidant vitamins (primarily Vit A and E but to a lesser extent Vit C) have long been touted as cardioprotective agents. There is some logic to this and a large industry of "cardiac health" nutritional agents has sprung up and been heavily promoted by alternative medicine proponents, nutritionists, chiropractors, dieticians, and physicians.

This study shows that there is no benefits to these supplements for cardiovascular protection and that most likely, they actually increase cardiovascular mortality.

Many of these nutritional agents will cease to exist or their use will be dramatically curbed as this information is more widely disseminated.

Analysis:  
The URL for this article is:

http://www.theheart.org/article/773375.do 

Coronary artery disease is not a simple calculation of the degree of blockage in an artery. It is well known that the clinical presentation is greatly influenced by the pro-inflammatory state of the patient.

This is why even patients with minimal coronary disease have heart attacks and those with high grade stenoses may not.

This concept is the rationale behind the "vulnerable plaque".

In an attempt to reduce the inflammatory state of the patient and to reduce "oxidative stress", many have proposed using large doses of the so called anti-oxidant vitamins E, A, and C.

Unfortunately, as with many such theories, the proposed benefits are not seen when the theories are tested in well designed clinical trials. In this particular case, supplemental doses of these vitamins actually increase cardiovascular mortality.

This underscores the need to test hypotheses in clinical trials rather than treating patients on anecdotal reports or consensus statements. Even well-intentioned nutritional advice should be taken with a grain of salt.

Implications:  
Tekturna is an oral, once daily medication which is the first renin inhibitor on the US market.

It inhibits renin directly and blocks the renin-angiotensin system at its initiation. This prevents buildup of angiotensin I and II and does not interfere with the kinin system.

In clinical trials, Tekturna has been shown to control BP as well as angiotensin receptor blockers and to have a better safety profile than ACE inhibitors.

This agent should see rapid adoption into the antihypertensive regimen of millions of patients whose blood pressures are poorly controlled. 

Analysis:  
The URL for this article is:

http://biz.yahoo.com/bizwk/070307/mar2007gb20070306897613.html?.v=1 

Tekturna is a novel agent that is an oral renin inhibitor.

It blocks the renen angiotensin system at its initiation and prevents accumulation of Angiotensin I and II. It does not affect the kinin system and therefore does not show many of the side effects seen with ACE inhibitors and ARB's.

If its efficacy and safety profile are consistent with the clinical trials, it should rapidly gain a large market share among patients with poorly controlled hypertension and those experiencing side effects from their current medications.

Implications:  
 There has been recent interest in natural orifice surgery as a new type of minimally invasive surgery. This has also been termed incisionless surgery because there are no noticible skin incisions.

This involves inserting surgical instruments via the mouth or anus to perform procedures in a similar fashion to the way endoscopic procedures are performed.

 These new devices are designed around an endoscopic platform but are able to perform more procedures including stapling and cutting as well as a type of suturing.

The stomaphyX device is being utilized to perform a type of bariatric surgery (stomach stapling) for weight loss that may gain popularity if the long term results are proven to be durable.

Endogastric solutions also makes an EsophyX device which can perform a type of anti - reflux procedure known as ELF which is similar to a surgical fundoplication.

Analysis:  
 The URL for this article is:

 http://www.medicalnewstoday.com/medicalnews.php?newsid=66889 

Additional information is available at:

 http://www.endogastricsolutions.com/ 

Endogastric solutions has developed 2 devices which are used for natural orifice surgery and can be used to perform a fundoplication (EsophyX) or bariatric surgery(StomaphyX).

Only StomaphyX is approved in the US at this time, but there will be many more devices available over the next few years if this is proven to be a viable approach for other procedures.

 The long term benefits and complications of these devices/ procedures are not yet proven, but they represent an exciting potential growth area for general surgery.

Implications:

Crestor (rosuvastatin) is an HMG CoA reductase inhibitor that blocks endogenous production of cholesterol.

Zetia (ezetimibe) blocks dietary cholesterol absorption from the GI tract.

The combination of these 2 agents has a significantly better result in reaching the recommended and optional ATP III goals than monotherapy with a statin (Crestor) alone.

Crestor is one of the more powerful statins on the market, but the combination of this with Zetia is significantly better than Crestor alone.

This should increase the use of both of these drugs since the combination reaches ATP III goals in 94% of patients and is relatively well tolerated.

Analysis: The URL for this article is:

http://www.medscape.com/viewarticle/554518

Crestor is a statin drug with powerful inhibition of the HMG CoA reductase enzyme.

Crestor has been shown to significantly reduce LDL cholesterol levels from baseline and compared to other statins.

Zetia combined with a statin has been shown to be more effective than the statin alone in several studies.

Adding Zetia allows more patients to reach goal in LDL management and may allow this with a lower dose of the statin. This could reduce the incidence of side effects such as liver damage or rhabdomyolysis.

Having the option of combination therapy should allow more patients to remain on Crestor therapy and could drive further sales of both drugs.

Implications:  
  The Food and Drug Administration approved only 17 new drugs last year compared to the peak of 53 approvals a decade ago.

 This is a direct consequence of the Vioxx controversy after the FDA was heavily criticized for the handeling of the approval and then withdrawal of Vioxx in 2004.

 Drugs and devices are having a harder time being approved in this climate of closer scrutiny to prevent subsequent withdrawals.

 This is the start of a new trend and will likely increase costs and time for approvals of drugs and devices.

Analysis:  
 The URL for this article is:

 http://www.nj.com/business/ledger/index.ssf?/base/business-0/116788960369140.xml&coll=1  


  The FDA is likely to require more data regarding cardiovascular side effects and larger pre-clinical and clinical trials before approving new drugs.

 While this may prevent problems such as those seen with Vioxx and Baycol, the delay of promising new drugs such as rimonabant (Acomplia) and several new anti-HIV and cancer drugs is frustrating to patients, physicians, and pharmaceutical companies.

 The recent canceling of torcetrapib is concerning since this particular drug may increase BP and cardiac mortality, but other drugs in this category still hold promise but may not be able to get through the approval process.

 Hopefully this pendulum will swing back toward the center in the near future.