Tamoxifen pharmacogenetics; GI cancers aren't sexy; vascular complications of splenectomy

Tamoxifen pharmacogenetics affects clinical outcomes

There is a growing list of drugs whose metabolism (and clinical effects) have been shown to be influenced by genetic mutations. (See my posts of March 1 and March 15, 2009: http://adrounysheme-o-gram.blogspot.com/2009_03_01_archive.html).

Besides important drugs like warfarin and clopidgorel (Plavix), tamoxifen effect has also been shown to be influenced by mutations of a metabolizing enzyme, in this case, cytochrome P450 2D6 (CYP2D6) enzyme.

The Oct 7 2009 issue of JAMA (http://jama.ama-assn.org/cgi/content/full/302/13/1429) features a German-American collaboration on clinical outcomes with tamoxifen stratified according to metabolizer type. Tamoxifen has been a foundation of breast cancer treatment for the last 30 years. Its growth inhibitory effect on breast cancer is mediated by metabolites 4-hydroxytamoxifen and endoxifen. The formation of these active metabolites is catalyzed by CP2D6. One hundred variants of CYP2D6 have been identified with four distinct phenotypes of metabolism: extensive (normal activity); intermediate (reduced activity), poor (no activity) and ultrarapid (high activity). A gene-dose effect has been demonstrated.

The study included almost fourteen hundred women from Germany and the U.S. with stages I, II and III who were given tamoxifen according to standard practices and who underwent pharmacogenetic analysis. Endpoints included standard oncologic parameters, including disease free survival and overall survival. Median follow-up was over six years.

The best results were seen in the extensive (normal activity) metabolizers. The overall recurrence rate was nearly double in the poor metabolizer group (24% vs 12.5%) and the death rate was significantly higher in the poor metabolizer group (22.8% vs. 16.7%)

This study is not the first to suggest an association between CYP2D6 mutations and clinical outcomes. However, it is the first with enough statistical power to actually prove the relationship.

The use of CYP2D6 testing is not yet a clinical standard. It may well become one. I have observed that at least one insurance company has been routinely demanding testing of patients who are prescribed tamoxifen.

An Interesting Comment

“For lack of a better word, GI cancers aren’t particularly sexy, certainly not from a political standpoint, nor is it easy to attract the blandishments of corporate largesse when the victims of these diseases comprise such a nebulous consumer base. Thus…it really falls on our shoulders to inspire and lead our patients and advocacy groups in an effort to increase funding, improve clinical trial participation, or incite a bit of a ‘riot’, if that’s what it takes to shatter insouciance and ensure that GI cancers get the attention they deserve…I strongly believe we can change the outlooks of patients with these terrible diseases…Our patients deserve better than run-of-the-mill interventions and should be demanding optimum treatment.”—John L. Marshall, M.D., Chief, Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University. Quoted in Gastrointestinal Cancer Research Volume 3 Issue 4.

Splenectomy induces a hypercoagulable state

Over 20,000 splenectomies are performed annually in the U.S. Besides a higher incidence of overwhelming sepsis, there are concerns about other potential long term complications of splenectomy. A recent article in Blood http://bloodjournal.hematologylibrary.org/cgi/content/full/114/14/2861 reviews the possibility that splenectomy induces a higher incidence of vascular complications.

Spleen contains white pulp and red pulp. White pulp is largely lymphoid tissue that processes antigens and produces antibodies. Red pulp consists of the sinusoidal cords of Billroth, which filter the blood by removing aged and damaged cells and by “polishing” red cells that have developed surface imperfections. The red pulp also contains a reservoir of platelets and granulocytes.

A number of potential vascular complications have been identified in post-splenectomy patients. These include arterial events such as stoke, M.I., carotid disease and peripheral arterial disease.

Venous events, both local and systemic, have been identified. The incidence of portal vein thrombosis after splenectomy ranges from 5 to 37%. Fatal pulmonary embolism was 5 times higher in persons with previous splenectomy than in matched controls in one autopsy study.

Pulmonary arterial hypertension is another potential vascular complication.

The authors speculate that the higher incidence of vascular events has multifactorial causes, resulting from hypercoagulability, platelet activation, disturbance and activation of the endothelium and altered lipid profiles. Absence of the filtration function of the spleen may permit particulates and cell debris to activate vascular endothelium. Splenectomy increases platelet counts, cholesterol, C-reactive protein, white count and hemoglobin concentration, all of which are associated with increased risks of arterial and venous thrombosis.

The authors conclude that further study of this is warranted, particularly with respect to issues such as whether short or long term thromboprophylaxis should be offered patients who have had splenectomy.

An alternative to warfarin for A. fib? ; The Great Influenza

Dabigatran for atrial fibrillation

The NEJM recently published a lead article (http://content.nejm.org/cgi/content/full/361/12/1139) which compared dabigatran to warfarin in patients with atrial fibrillation. Dabigatran belongs to a new class of oral anticoagulants known as DTI’s (direct thrombin inhibitors) which are in development. (See my Heme-O-Gram of Dec. 14 ’08 http://adrounysheme-o-gram.blogspot.com/2009/03/new-oral-anticoagulant-drugs-report.html )

While the effectiveness of warfarin for stroke prevention in atrial fibrillation is in little doubt, warfarin is probably underutilized because of a number of reasons primarily relating to inconvenience and risk of bleeding. Drugs like dabigatran offer several advantages over warfarin: fixed dose, shorter half-life, no need for monitoring, wide therapeutic index, oral administration, general convenience. The question is whether it meets non-inferiority with a tried and true agent like warfarin. Previously, dabigatran was shown to be as effective and safe as enoxaparin (Lovenox) in reducing VTE after orthopedic surgery.

The RE-LY (Randomized Evaluation of Long-Term Anticoagulation) trial, which accrued and randomized over 18,000 patients, the standard of non-inferiority for atrial fibrillation appears to have been met with respect to the primary outcome, either stroke or systemic embolism. The study was funded by Boehringer Ingelheim, the manufacturer of dabigatran. Two doses of dabigatran were studied: 110 mg and 150 mg each given b.i.d. The 18,000 patients were evenly matched across the three study groups.

The lowest rate of stroke/systemic embolism occurred in the group receiving dabigatran 150 mg bid (1.11. % per year compared to 1.69% for warfarin and 1.53% for dabigatran 110 mg bid.) Both dabigatran doses were non-inferior to warfarin but only the higher dose was superior. Bleeding rate was highest in the warfarin group (3.36% per year) and lowest in the dabigatran 110 mg bid group (2.71% per year). In the dabigatran 150 mg bid group, the rate was 3.11% per year.

The only significantly increased adverse effect in the dabigatran treated patients was dyspepsia. There were higher rates of myocardial infarction in the dabigatran groups, but not statistically significant. The authors hypothesize that warfarin may have a more protective effect in coronary disease than dabigatran.

There were also higher rates of discontinuation in both dabigatran groups, apparently because of GI symptoms and other unspecified serous adverse events. The authors do not go into any detail to explain the latter.

The quality of warfarin administration was good, as evidenced by a 64% rate of therapeutic INR in the warfarin treated group.

In conclusion: dabigatran appears to be non inferior to warfarin both in terms of efficacy and complications for prophylaxis of stroke and systemic embolism in patients with atrial fibrillation. As part of a new class of oral anticoagulants, dabigatran appears to be headed towards approval for use in a variety of settings. Keep yours eye open for this new drug.

Hemorrhagic complications of influenza

“Then there was the blood, blood pouring from the body. To see blood trickle, and in some cases spurt, from someone’s nose, mouth, even from the ears or around the eyes, had to terrify.

“One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred.

“One German investigator recorded ‘hemorrhages occurring in different parts of the interior of the eye’ with great frequency. An American pathologist noted: ‘Fifty cases of subconjunctival hemorrhage were counted. Twelve had a true hemoptysis, bright red blood with no admixture of mucus…Three cases had intestinal hemorrhage…’

These frightening descriptions of “the flu” come from the book The Great Influenza by John M. Barry, an outstanding treatise on the history of the 1918 flu pandemic and the history of American medicine and its response to the medical emergency posed by the pandemic. With current concerns about H1N1 virus, it made me wonder if we might expect similar dramatic clinical manifestations.

But surprisingly (and happily), clinical descriptions of the current H1N1 flu outbreak, which conceivably has the potential to reach pandemic levels, are surprisingly tame with respect to hematologic complications. Both mild leukocytosis and leucopenia have been seen according to reports. A substantial incidence of pulmonary embolism was reported in five of 10 ICU patients hospitalized with H1N1 and ARDS in Michigan and “hypercoagulable state” was reported to be evident in two additional patients. Otherwise, there seems little to report. I will keep watch on this.