Wednesday, June 13, 2012

Pradaxa: The Science Behind the Medicine—Part Two

Delivery System of Pradaxa

As a continuing discussion of the science behind the medication Pradaxa, used in the treatment of atrial fibrillation, it is believed that the high incidence GI issues experienced in Pradaxa users relates directly to its unique delivery system. Pradaxa is absorbed most readily when low pH levels are present. Each Pradaxa capsule contains hundreds of small pellets, each with a core of tartaric acid. Tartaric acid is a white crystalline organic acid which occurs naturally in grapes, bananas and tamarinds and is also one of the primary acids found in wine.

Tartaric acid is typically added to foods to provide a sour taste or used as an antioxidant. Pradaxa incorporates the tartaric acid core in their medication in order to produce an acidic environment in the body which facilitates absorption. The acidity produced is also likely the primary reason Pradaxa can lead to GI symptoms and subsequent GI bleeds. In fact, those taking Pradaxa who suffered from gastrointestinal issues such as dyspepsia and heartburn were three to four times as likely to eventually suffer a serious gastrointestinal bleed. Some studies have indicated that the chemical characteristics of tartaric acid may cause undiagnosed ulcers or other GI bleeding events to change from once-unnoticed bleeds to serious threats.

A Pradaxa etexilate coating is applied over the tartaric acid core and is believed to create a more consistent absorption in an acidic environment. What this means is absorption of Pradaxa is not dependent upon the individual’s unique gastrointestinal environment rather it creates its own optimal pH environment. This artificial creation of a constantly acidic environment is likely the primary cause of the GI side effects which lead to gastrointestinal bleeds.

Pradaxa and Renal Functioning

Up to 80% of Pradaxa is eliminated through the kidneys, therefore in those who have any type of renal dysfunction a higher concentration of the drug will likely be found in the body. Warfarin is not excreted through the kidneys which is why frequent monitoring is necessary in order to properly adjust the dosage. Since kidney functions often decline among the elderly, this is likely why the RE-LY trial showed a correlation between the elderly taking Pradaxa and excessive bleeding events. It is believed, however, that other factors associated with aging may also play a part in negative symptoms stemming from Pradaxa use.

The concentrations of Pradaxa found in those patients who took part in the RE-LY study increased as much as 30% in those over the age of 75 as compared to those aged 65-75 and was 68% higher than those younger than 65. Since the anticoagulation effect of Pradaxa is definitely dose dependent, it is believed that any type of kidney dysfunction along with advanced age while not actually causing bleeding events could definitely exacerbate them. The gastrointestinal bleeding found in the lower GI tract is believed to be definitively tied to the Pradaxa delivery method as it moves through the digestive tract.

Pradaxa’s Active Ingredient

Following oral ingestion the active ingredient in Pradaxa, Dabigatran, has a low bioavailability level. It is possible that the enzymes in the body which metabolize Dabigatran can lead to increasing levels of concentration of the drug as it travels through the gastrointestinal tract. In plainer terms this means it is difficult to get the drug out of the GI tract and into the bloodstream, therefore the pellets inside the capsule are being dissolved as they pass through the GI tract. This direct exposure to the drug Dabigatran significantly increases the prevalence of diverticulosis and GI bleeds. Warfarin, as opposed to Pradaxa has a very high bioavailability level and unabsorbed Warfarin will not cause bleeding due to the fact that Warfarin requires hepatic enzyme metabolism before the anticoagulant effect kicks in.

Who is Most at Risk?

All studies indicate that particular care should be taken among those over the age of 75 who are taking Pradaxa or in patients who have a history of kidney disease or GI bleeds. Whether the elderly should be more completely screened prior to be placed on a drug with no known antidote to excessive and potentially fatal bleeding remains the primary question regarding the safety of Pradaxa. This particular population has a greatly increased risk of previously undiagnosed pathologies becoming agitated to the point of initiating a serious, life-threatening bleed. Because of the fact that patients who experienced any gastrointestinal side-effects while taking Pradaxa were three to four time more likely to develop serious GI bleeds, the patient instructions which come with Pradaxa do not indicate this.

The physician instructions for Pradaxa do mention the fact that patients should contact their doctor if they suffer any gastrointestinal side effects, however it is likely that not all doctors convey this information to their patients. The information included with Pradaxa does presently mention that like all anticoagulants, patients taking the drug should be vigilant in looking for any signs of bleeding, although patients are also advised not to stop taking Pradaxa suddenly as this could lead to an increased risk of stroke. Many experts believe the warnings and instructions are entirely insufficient and the wording should be changed to reflect the potential dangers.

Does Pradaxa Bring an Increased Risk of Heart Attack?

A recent study raised the issue of increased heart attacks among those patients taking Pradaxa. WebMD reported online that as compared to Warfarin, Pradaxa posed as much as a 33% increase in the risks of a serious heart attack. While the manufacturer of Pradaxa, Boehringer Ingelheim, issued a statement which claimed only a very small increase in heart attack risk for those taking Pradaxa, patients with a history of heart disease or have had a prior heart attack should definitely speak to their physician prior to taking Pradaxa. A meta-analysis of Pradaxa associated its use with increased odds of myocardial infarction or acute coronary symptoms than the control treatments. In short, while Pradaxa does appear to significantly reduce the risk of strokes, those with a prior history of heart disease, the elderly, or those with any type of impaired kidney function should definitely exercise caution before starting a Pradaxa regimen.

Author: Sullo & Sullo Attorneys

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