Yesterday, Fresenius SE, a German company and the largest worldwide provider of dialysis services, announced that it has agreed to buy the U.S. company APP Pharmaceuticals for $23 cash a share, plus as much as another $6 a share if APP's financial results meet certain targets, resulting in a purchase price ranging from $3.7 to $4.6 billion. (WSJ: Market Watch, 07/07/08, "APP to be Bought by Fresenius for up to $4.6 Billion.") In addition, Fresenius agreed to assume APP's $940 million of debt, net of the company's cash on hand. (Id.)

After the Baxter recall of contaminated heparin, APP became the leading producer of heparin. (WSJ, 02/19/08, "Baxer Rival APP Steps in Quickly to Supply Heparin.")

Analysts opine that the sale will allow Fresenius to "take control of heparin," and "curb the rise in its price." (Reuters, 07/07/08, "Fresenius to Enter World Drug Market with APP.") As a result, Fresenius' U.S. rival, DaVita, Inc., could "'ride the coattails' of that price moderation." (Id.)

The company will become part of the Fresenius Kabi division, a provider of infusion therapy services in Europe, Latin America and Asia.

Much is yet to be learned regarding the contaminate found in the recalled heparin, oversulfated chondroitin sulfate (“OSCS”). However, the first and only study published to date since the January 2008 heparin recall does shed some light on the relationship between the contaminate and the severe reactions, sometimes fatal, experienced by many Americans. (“Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System,” N. Engl. J. Med. 358:23, pgs. 2457-2467, June 5, 2008, available for a charge on the New England Journal of Medicine Website.) One of the issues addressed in this article is a question that we are often asked by our clients, why weren’t all patients who received tainted heparin from a particular lot affected?

In order to investigate this and related issues concerning the biologic link between the contaminant and the reported reactions, the researchers conducted animal testing. (6/5/08 N. Engl. J. Med. article, pg. 2464.) Pigs were chosen because unlike rabbits, horses and rats, only the pig plasma supported an appropriate level of response to the OSCS contaminated heparin, but not the uncontaminated control heparin. (This also may explain why early attempts by Baxter to provoke an allergic response with suspect lots of heparin failed. See Baxter 03/19/08 Press Update and 6/5/08 N. Engl. J. Med. article, pg. 2464.)

The pigs were given a single intravenous dose (5 mg per kilogram) of OSCS-contaminated heparin, uncontaminated heparin, or other substances. (06/05/08 N. Engl. J. Med. article, pg. 2466.) They were then monitored for 60 minutes. Two of six pigs treated with OSCS-contaminated heparin had at least a 30% drop in blood pressure over the first 30 minutes after infusion. One animal remained in a hypotensive state for more than 15 minutes. In contrast, none of the four animals treated with uncontaminated heparin showed any substantive changes in blood pressure. (Additionally, three pigs were given pure synthetic OSCS. All three of these pigs “showed a profound drop in blood pressure [maximal decrease, 45 to 59%] and a concurrent increase in heart rate within minutes after infusion.”)

Interestingly, while not all pigs who received OSCS-contaminated heparin exhibited clinical signs, the researchers found that “induction of kallikrein activity [kallikrein is an enzyme present in blood plasma and other body fluids which can lead to the generation of bradykinin that in turn, impacts the blood vessels leading to hypotension and other symptoms] was evident in all animals that received OSCS-contaminated heparin, even when no substantive changes in blood pressure were observed.” (06/05/08 N. Engl. J. Med. article, pg. 2466, with explanation and emphasis added by Zoll, Kranz & Borgess, LLC.) Based on these findings, the researchers concluded as follows:

“These findings suggest that activation of kallikrein does not always manifest as clinical symptoms, perhaps because of individual variations in control mechanism that regulate bradykinin activity…. The finding that hypotension did not develop in all animals treated with OSCS-contaminated heparin, even at a relatively high dose, is consistent with the observation that the majority of patients who received contaminated heparin did not experience an adverse event. However, it is important to note that all animals treated with OSCS-contaminated heparin showed evidence of kallikrein activation in vivo, even in the absence of clinical signs. Patients undergoing dialysis who are also receiving heparin therapy are already at high risk for hypotension because of their exposure to the dialysis membrane, which can also activate the contact system, and their treatment with angiotensin-converting-enzyme inhibitors, which inhibit bradykinin degradation. Exposure to OSCS-contaminated heparin may further increase the risk and could potentially trigger an adverse event.” (06/05/08 N. Engl. J. Med. article, pg. 2467.)

Thus, the scientific evidence to date suggests that while some patients may not exhibit clinical signs after receiving OSCS, this does not necessarily lead to the conclusion that those patients were “unaffected” by the OSCS, particularly those patients, including dialysis patients, who are already at greater risk.

Hopefully, researchers will continue to investigate the relationship between OSCS and the reported reactions, so that the families of those who have lost loved ones can understand how and why this happened, and continue to hope that it can and will be prevented in the future.