Genetically informed therapy and technical innovations in cardiology

I want to give an overview of cardiac care advances – the first two themes are discussed here. I want to thank Dr. Mandeep Mehra, chief of cardiology at the University of Maryland for conceptualizing these themes for me.

First is genetically informed therapy. Pharmacogenomics is having an impact in the use of warfarin (Coumadin) and clopidogrel (Plavix). Warfarin dosage can now be titrated in part based on a person’s genomic makeup. In at least one study the incidence of hospitalization in the six months after initiation of warfarin, hospitalization was reduced by 31% overall and by 28% for bleeding and thromboembolism as a result of dosage modification with genomic testing. Clopidogrel is metabolized to its active metabolite by one of several polymorphic CYP450 enzymes. One of these is CYP2619 which can affect platelet activity. It has multiple alleles which convey much different rates of metabolism and hence anti-platelet activity. Lessened metabolism has been associated with increased major cardiovascular events such as stent thrombosis. So treatment with this drug can be improved on a personalized basis with pharmacogenomic analysis.

Genomics is also important in tests for those with the Long QT Syndrome as differing genes lead to differing clinical patterns which in turn can be triggered by differing stressors such as anxiety or exercise. Hypertrophic cardiomyopathy (HCM) is caused by mutation in a gene that codes for proteins in cardiac muscle. Testing in families with a member who has HCM can detect those at risk at an early age. In the future there may be approaches to prevent the progression from genotype to phenotype, perhaps with an inhibiting targeted drug.

A very recent study has shown that sporadic thoracic aneurysms are associated with a mutation in the fibrillin 1 (FBN1) gene suggesting a common etiology. Armed with this knowledge it may be possible for an inhibitor drug such as angiotensin II receptor antagonist losartan (Cozaar) to block FBN1 action and thereby prevent progression to aneurysm or from aneurysm to dissection. Another recent study (both of these are at Nature. 11 Sept 2011 [Epub ahead of print]) of about 200,000 individuals with hypertension using genome wide analysis has detected 29 different genomic loci that associate with elevated blood pressure including many genes not previously implicated. This knowledge may well lead to new drugs for treating hypertension in the future.

The second theme is technical innovations, mostly medical devices as discussed in my two prior posts. This includes percutaneous placed left ventricular assist devices (LVADs) that can be used for seven to 10 days or more to allow the heart muscle to rest – “facilitated healing of the heart.” Also are the percutaneously placed aortic valves and mitral valve repairs, implanted heart monitors that watch for potassium flux associated with arrhythmias and left atrial appendage leads to monitor for atrial arrhythmias, especially paroxysmal atrial fibrillation.

There are some new drugs as well that show significant innovation such as those to replace warfarin. Warfarin has been used for decades (since 1954) to reduce the incidence of embolic stroke among patients with atrial fibrillation but it is plagued by the risk of serious bleeding plus the need for frequent monitoring with dose adjustment. There are three new drugs that have recently been studied in large groups of patients – apixaban, dabigatran and rivaroxaban – that may offer a major advance. These are direct thrombin or Xa factor inhibitors which do not require dose monitoring. Each of these in large randomized controlled trials have been show to reduce the incidence of stroke below that of warfarin and, importantly, reduce the frequency of bleeding including hemorrhagic stroke. The risk of death from all three new drugs was about 10% less then among those treated with warfarin.

For example, in the apixaban trial of 18,000 patients, the risk of stroke or systemic embolization was reduced by 21%, major bleeding by 31% and death by 11% when compared to warfarin. Most of the added stroke prevention value was in less hemorrhagic strokes. While these results are striking it need to be remembered that the risk of stroke on warfarin was about 1.6% per year, a not trivial number but a 21% reduction still leaves the risk at nearly 1.3%. Similarly the annual risk of major bleeding was about 3.1% on warfarin and was reduced to about 2.1% with apixaban. The cost of these three on patent drugs will far exceed that of warfarin but the efficacy and safety profile along with the convenience of not needing regular monitoring will compete with cost to decide who will be switched to one of the newer drugs.

Also on the horizon are drugs aimed at elevating high density lipoprotein (HDL) but there seems to be little progress in developing new drugs for arrhythmias.

Stephen C. Schimpff is an internist, professor of medicine and public policy, and former CEO of the University of Maryland Medical Center.  He is the author of The Future of Medicine — Megatrends in Healthcare and blogs at Medical Megatrends and the Future of Medicine.

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