ARTICLE OF THE MONTH: THE ROSIGLIZATONE STORM: Rosiglitazone and Increase Risk of Coronary Artery Disease.

This is one of the biggest controversies medical science has seen in recent times. There have been reports that the popular Anti Diabetic Drug ‘Rosiglitazone’ increases the risk of Myocardial Infarction. Dr. Om Lakhani analyzes the background and the current status of this controversy.

Sources

• “The Rosiglitazone Controversy: Indian Perspective” : V Mohan, S. Joshi: Editorial JAPI Volume 55: July 2007
• Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.
• Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; June 5:[Epub ahead of print]
• Krall RD. Cardiovascular safety of rosiglitazone. Published online
• Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJV. For the RECORD Study Group. Rosiglitazone Evaluated for Cardiovascular Outcomes - An Interim Analysis. N Engl J Med 2007; June 5:[Epub ahead of print]
• Drazen JM, Morrissey S, Curfman GD. Rosiglitazone – Continued Uncertainty about safety. N Engl J Med 2007; June 5:[Epub ahead of print]
• Nathan DM. Rosiglitazone and cardiotoxicity – weighing the evidence. N Engl J Med 2007; June5:[Epub ahead of print].

Psaty BM, Furberg CD. The Record of rosiglitazone and the risk of myocardial infarction. N Engl J Med 2007; June 5:[Epub ahead of print].


Q. What are “Glitazones” or “Thiazolines” and why have they been always in the news ?

Ø “Glitazone” or “Thiazolidines” the popular anti diabetics have always been in the news for reasons right or wrong
Ø Glitazones are wonderful antidiabetic drugs because they reduce the Insulin Resistance. Insulin Resistance as we know is the main pathological factor in Type 2 Diabetes Mellitus.
Ø It was widely used after its introduction but then came the first big controversy.
Ø About 63 deaths were reported in US due to hepatotixicity caused by earlier products from this family. The US FDA withdrew the drug from the market.
Ø But popular demand made this group of drugs come back in newer safer versions as ‘Rosiglitazone’ and ‘Pioglitazone’
Ø Because of their history they were always viewed with suspicion and the FDA had asked the doctors to regularly monitor the hepatic functions of their patients who were prescribed these medications.
Ø But the drugs turned out to be safe and did not cause hepatotoxicty.
Ø Because of this new found safety this group of drugs widely rose in prominence.
Ø In recent time two trials DREAM and ADOPT have went on to suggest that it is time we start using them as first line agents.
Ø But then came the big storm after a meta analysis submitted in New England Journal of Medicine questioned the safety of Rosiglitazone once again. (more on in it is given below)

Q. What are the know side effects of Rosiglitazone ?

Rosiglitazone and Pioglitazone are known to cause the following side effects.

Pedal Odema
Weight gain
Reduced Hematocrit
Fluid Retention.

Q. What is the recent controversy about Rosiglitazone that created a storm in the medical circles ?

Ø The recent controversy about Roiglitazone came forward after a meta analysis published in New England Journal of Medicine by Nissen et al reported an increase risk of Coronary Artrey disease and Myocardial Infarction on usage of Rosiglitazone.
Ø They concluded on studying 42 trials that

Rosiglitazone Increases risk of MI by 42%
It increases the risk of Death due to Cardiovascular event by 64 %

Ø This study was widely reported in Lay press and hence created a lot of anxiety in patients already taking this drug.

Q. Why was this reported viewed with suspicion ?

Ø Meta-analysis by nature are two weak to conclude anything major
Ø Many question Meta-analysis per se and even those who do believe in them have questioned the way this one was carried out.
Ø Analyses of the 42 studies showed that 40 of them were small and all these put together did not yield statistically significant difference for myocardial infarction (MI) between groups.


Ø Responding quickly to the metaanalysis by Nissen et al , the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study investigators did an unplanned interim analysis of their results two years before the study was scheduled to conclude.
Ø The results indicated no statistically significant differences in the overall risk of hospitalization or death from cardiovascular causes between the study groups

Ø The results were (not surprisingly) inconclusive as this is an interim analysis after 3.75 years of median follow up and thus lacked adequate power as the original analysis was planned to be done after 6 years of median follow up.

Ø From a purely statistical perspective, these results would indicate a slight increase in risk for MI / coronary artery disease among subjects on rosiglitazone.
Ø However, a closer analysis of these data would indicate that the presently available data are not conclusive as none of the studies had cardiovascular disease (CVD) as primary end-points except RECORD.
Ø In the RECORD study, only an interim analysis was published which had inadequate power to assess CVD outcomes.
Ø Several Societies like the American Diabetes Association, Endocrine Society in the US, American Association of Clinical Endocrinologists have come out with statements urging physicians and patients not to panic and stop the medication but to undergo a reevaluation by their treating physicians and make decisions with them.
Ø Even the US FDA has not withdrawn the drug but asked for strict review and some changes have been made on the prescription label.
Ø The EU regulatory agencies have also not withdrawn the drug.


Q. So what should the conclusion and what should be done now ?


The Editorial in recent edition of JAPI advices the following for the Indian Physicians:

1. Reassure patients and physicians that there is nothing to panic.
2. Advise patients not to abruptly stop their medications but discuss it with their physician and under medical supervision of experts decide on case to case basis a plan which meets patient’s safety and therapy concerns.
3. Ensure that current glycemic control & non glycemic comorbid conditions are validated by not just fasting and postprandial blood glucose but do a glycosylated hemoglobin test, lipid profile,hematocrit and electrocardiogram(with or without an echocardiogram)
4. If they have established heart disease, it may be worthwhile to discuss with their physician / cardiologist about stopping the drug and appropriately adjusting their anti-diabetic medications.
5. If the physician is convinced about any concern then there are other options available in the same class, other class as well as Insulin. Both options need patient education and physician supervision to ensure patient safety risk as well as the glycemic control is well balanced as well as monitored periodically.
6. New patients with type 2 diabetes at risk of heart disease could probably be given alternate drug therapies until further evidence emerges with respect to the safety of this class of drugs.
7. Strict adherence to CVD risk reduction i.e. Aspirin (or Clopidrogel), Statin, ACE (or ARB) inhibitors, weight reduction, tighter glucose and BP control and stricter cardiac evaluation in all diabetic patients.
8. Individualized comprehensive evaluation and cardioprotective measures can be re-addressed and its an ideal opportunity for patient education to ensure that they are in control of their diabetes and vascular risk.

Guidelines for Use of Antiretroviral Therapy for HIV Infected Individuals in India (API ART Guidelines) 2007

Guidelines for Use of Antiretroviral Therapy for HIV
Infected Individuals in India (API ART Guidelines)
2007

Click the link below to Download the LATEST pdf file. A Summary Version of This coming soon.

http://www.japi.org/july2007/api_Art_Guidelines_new.pdf

How Common Is Needlestick Injury ?

(Needlestick Injuries among Surgeons in Training, Martin A. Makary, M.D., M.P.H. et al, New England journal of Medicine. Volume 356:2693-2699 June 28, 2007 Number 26 )

How Common is needlestick injury amongst Residents ? Here are some intersting facts about needlestick injury collected from an article published in New England Journal of Medicine .

1. 99% of Surgical Residents have reported atleast 1 needlestick injury in their period of training
2. As expected Surgical Residents are more likely to have an injury than Medical Residents
3. A Shocking 51% of Injuries are not reported.
4. Double Gloving reduces the risk of exposure to blood significantly.
5 .Sharpless surgical practices are new methods for reducing this menace
6. If anti retroviral therapy is taken within 24-36 hrs , it reduces the incidence of Needlestick injury by 81%

Gardasil: New Vaccine that Prevents Cervical Cancer

(HPV Vaccine , Joan Stephenson, PhD , JAMA. June 2007;297:2578)

Q. Can Cervical Cancer be prevented ?

• Cervical Cancer is commonly caused by HPV strains 16 and 18
• A new vaccine "Gardasil" manufactured by Merck Pharma prevents infection by these strains hence deemed useful in preventing cervical cancer
• The vaccine is not effective in preventing cancer in women who are already infection by HPV, hence routine screeing for Cervical cancer cannot be substituted.

New Guidelines for Hemorraghic Stroke.

(Hemorrhagic Stroke Guidelines Issued , Mike Mitka , JAMA. June 2007;297:2573-2575. )


Q. Which new drug is said to bring a revolution in management of Hemorraghic stroke ?

Recombinant Activated Factor VII (NovoSeven- Novo Nordisk) – this drug reduces the bleeding and hence is likely to reduce the growth of hematoma. Trials are on for this and is increasingly used in advance setups for Hemorraghic stroke. This drug is likely to bring a revolution in management of Hemorraghic stroke.


Q. When is CT Scan Better than MRI and MRI Better than CT in Diagnosis of Hemorraghic Stroke ?

CT better than MRI

• Show associated extension of stroke into the ventricles
• In patients who are unconscious, vomiting or on ventilator
  
  MRI better than CT
• Detecting Underlying Structural lesions
• Small Prior hemorrhages

Important CLASS I and CLASS II Recomedations of the Guidelines

The guidelines' class I recommendations (based on evidence for and/or general agreement that the intervention is useful and effective) specify always treating seizures in patients with hemorrhagic stroke with appropriate antiepileptic therapy and treating fever.

The document's class II recommendations (for which evidence of the intervention's usefulness/efficacy is less well established and is based on conflicting evidence and/or a divergence of opinion) include
¬ using a balanced and graded approach to treating elevated cranial pressure,
¬ starting with head-of-the-bed elevation,
¬ analgesia,
¬ and sedation;
¬ treating hyperglycemia;
¬ treating hypertension to target blood pressure levels using a variety of medications including Nicardipine;
¬ and treatment with recombinant activated factor VII within the first 3 to 4 hours after onset, but only in a clinical trial setting, as efficacy and safety must still be confirmed.

Q. What is the Role of Surgery in Acute Hemorraghic Stroke ?

The Role of Surgery in Hemorraghic Stroke is Controversial. The 2007 STICH Guidelines (International Surgical Trial in Intracerebral Hemorrhage ) recommendations are included in the current guidelines which are.

Absolute Indication for Surgery (Class I)

• Hemorrhage > 3cm
• Detoriating Neurologically
• Brain Stem Compression
• Hydrocephalus from Ventricular compression
  
  Relative Indication (Class II)
• Surgeons should consider evacuating lobar clots 1 cm from head surface by standard craniotomy
  
  Q. What is Ultra early Craniotomy and what is its role in Management of Hemorraghic stroke ?
  ¬ Ultra Early craniotomy is performing a surgery within 12 hrs of onset of stroke.
  ¬ This is found to have no clear evidence of benefit to moratlity in the guideline
  ¬ Infact on the other hand it may increase the risk of recurrent rebleeding

Q. What is Endocsopic Aspiration and what is its role ?

¬ Another intervention of interest involves endoscopic aspiration. It means placing catheters into the clot and sucking it out more gently and without going through too much brain
¬ There has been some positive glimmering, but nothing definitive according to the guidelines
¬ The new guidelines give endoscopic aspiration a class II recommendation, based on a small, single-center randomized trial of 100 patients.
¬ That study found patients whose clots (at least 10 mL in volume) were removed had better outcomes than those treated with medicine only (Auer LM et al. J Neurosurg. 1989;70:530-535).
¬ Endoscopic aspiration of smaller clots led to significantly better quality of life, but survival was similar to those in the medical group
¬ benefit was mostly limited to patients with lobar hematomas and those younger than 60 years.


Q. What are the Guidelines on End of Life Care in such patients ?

¬ But the guidelines advise treating such patients aggressively in the first 24 hours to see what happens, and then to make end-of-life decisions.
¬ This allows time for the physician, family, and patient to think about what is happening.

Management of Early Rheumatoid Arthritis

(Management of Early Rheumatoid Arthritis: E Suresh, Journal of the Association of Physicians of India JAPI, Volume 55, May 2007)

Q. What has been the ideological shift in management of Early Rhematoid Arthritis ?

In the earlier time the philosophy was “Go Slow, Go low” which means drugs were added in a pyramidal system, NSAIDS followed by DMARDS followed by Steroids. Now the idea is to start treating Rheumatoid Arthritis aggressively by starting DMARDs early. This is because it has been found that irreversible damage occurs to the joints once the window of opportunity in treatment in early Rheumatoid arthritis is lost when the inflammation is still active.

Q. What is the role of Cyclic Citrullinated Peptide (CCP) in early diagnosis of RA ?

CCP is an early marker of RA. Its prevalence in blood precedes symptoms of RA by years !

Q. How will you manage a patient with Early Undifferentiated Inflammatory Arthritis ?

Since the American Rheumatology Guidelines suggest that the symptoms must persist for 12 wk for diagnosis of RA, hence we cannot accurately diagnose a person to have Rheumatoid arthritis before that period passes. And yet like mentioned before, the window of opportunity presents early, hence to resolve this conflict trials are underway to Stop RA Very Early or SAVE trial.

According to the article if a patient presents with Rheumatoid like Polyarthritis early :

If multiple joints are involved give 120 mg of Methyl Prednisolone deep IM
If fewer joints are involved Intrarticular steroids are useful.

If Remission is not achieved for 12 wks patient is classified as having RA and started on DMARDs.

Q. Which are the best DMARDs to start with ?

Methotrexate, Sulphasalazine and Leflunomide are suggested as first line agents for monotherapy by the article.

Practical Pearl : Patients on Methotrexate should be discouraged to take alcohol.

Q. Are DMARDs safe in Pregnency ?

Methotrexate and Leflunomaide are proven teratogens. They are absolutely contraindicated in pregnancy. Patients should be off methotrexate for 3 months before they conceive. Cholestyramine or activated charcoal should be used for patients on Leflunomide to wash it off .

Sulphasalazine is relatively safe in pregnancy, though higher dose of folic acid should be prescribed.

Q. What is DAS score ?

DAS score or Disease activity score is an important parameter for monitoring prognosis of patients of RA. (See http://www.dasscore.nl/ for details. )

Score >5.1 suggests high disease activity

Q. What is the role of Infliximab ?

Infliximab is an Anti-TNF agent. It has been proven to be effective in RA. If given it is combined with Methotrexate. It gives remission of upto one year on stopping therapy. The article suggests that currently the use of Infliximab is limited to research settings due to its high cost.


Important Notice: It has been proven that COX-2 inhibitors (Coxibs) increase risk of MI, Stroke and Thrombosis

Q. What is most important contraindicated to intrarticular steroid injection ?

Septic Arthritis is an important C/I to Intraarticular steroid injection.

While injecting IA steroids care should be taken not to inject > 3 joints in one sitting and same joint not more than 3-4 times a year.

Q. Does Alternative medicine help in RA ?

Gamma linoleic acid, an important component of Ayurvedic drugs for RA is found useful in RA. Mediterranean diet, Vegetarian diet , Fish oil supplementation and Yoga are other alternative therapies found useful.

Q. What is the most important cause of death in patients with RA ?

Accelerated Atherosclerosis.

Low Molecular Weight Heparin in Viper Bite

(Trial Of Low Molecular Weight Heparin in the Treatment of Viper Bites: Paul V, Pudoor A et al. Journal of the Association of Physicians of India JAPI, Volume 55, May 2007)

Q. Should Low Molecular Weight Heparin (LMWH) be used in Viper Snake Bites ?

Yes. Viper venom is hematotoxic and increase the bleeding tendency yet LMWH which also increase bleeding tendencies is used in Viper Snake bite ! This is because one of the biggest problems with Viper snake bite is that it causes DIC (Disseminated Intravascular Coagulation), LMWH prevents DIC. Hence it is logical to use Heparin in Viper Snake bites. A study done by Paul, Pudor et al published in May 2007 in JAPI proves this to be true. They found it LMWH reduces the mortality and morbidity in patients with Viper bites.

Q. What are the two leading cause of death in patient with Viper bite ?

Hypotension and Acute Renal Failure are the two leading causes of death in patient with Viper Bite, both of which can be caused by DIC.

Q. Where does LMWH act ?

LMWH acts on Factor Xa in coagulation cycle

Q. What are the advantages and Disdvantages of LMWH over Unfractionated Heparin ?

LMWH has less chances of severe bleeding episodes than unfractionated heparin. Also it has better absorption through subcutaneous route and has not effect on platelets.Also LMWH does cause Nitrous oxide (NO) release from the vascular endothelium which is the culprit in causing hypotension.

The biggest drawback of using LMWH in viper bite patient compared to UFH (other than the cost which is substantially high for LMWH) is that it doesn’t prevent microvascular thrombosis which is an important cause of Renal failure in such patients. This is what they found in the study. LMWH couldn’t prevent renal failure like UFH could.

Conclusion : It is a good Idea to Use Low Molecular Weight heparin in patients with Viper Snake Bite.