Posts Tagged ‘Acute Coronary Syndrome’
What does PLATO give us?
The FDA recently received the submission for a new drug ticagrelor for the treatment of Acute Coronary Syndrome. As mentioned before, this syndrome is a significant cause of death in the United States. One in three who suffers from it will have death or another myocardial infarction within a year. Its effective treatment is vital to our war on cardiovascular death and disability.
Ticagrelor is an oral reversible direct acting inhibitor of the P2Y12 platelet activation site. This sentence tells you much about the difference between this drug and the other two agents; clopidogrel and prasugrel. Ticagrelor is reversible and they are not and this drug is a direct action agent and it is not metabolized into the effective agent so it has no biologic variability as clopidogrel does.
Ticagrelor was tested against clopidogrel in 18,624 who had acute coronary syndrome with and without ST segment elevation. The Plavix group received a 300mg loading dose (the standard at the time the study was done) and then 75mgs a day for one year. The ticagrelor group received a 180mg loading dose and then 90mg twice a day.
At twelve months the primary endpoint which was death from vascular causes, myocardial infarction or stroke had occurred in 9.8% of the ticagrelor group and 11.7% of the clopidogrel group. This yielded a statistically significant result P<0.001. No differences were found in rates of major bleeding 11.6% vs. 11.2% but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting 4.55 vs.3.8%.
This result is different from that of prasugrel, which had better outcomes but at the expense of more bleeding episodes. This likely stems from the fact that it is better metabolized that Plavix and so “more effective.” Another “good and bad” feature is that the effect on the platelet is short lived and that is why it must be taken twice a day.
It remains to be seen if patients will accommodate that. In general, most patients in my experience like once-a-day drugs. This drug is twice-a-day and “missing” it may lead to more stent thrombosis in general practice. Often patients are more “compliant” in studies and don’t live with the real world problems of obtaining their drugs by seeing the doctor or having to deal with Insurance companies that want to change from one drug to another.
This compound does give us the ability to change from Plavix to Brilinta in those patients who will require surgery and allow us to “load” patients in the Emergency room. Over all this is an advance in the treatment of coronary disease. I am sure that next will be a member of this class that is once a day. Slowly but surely we are improving the outcomes of patients with acute coronary syndrome.
And Away Goes Trouble Down the Drain…
In the middle ages, Alchemists dreamed of transmuting coal into gold. In much the same ways Cardiologists have dreamed of a substance that would remove plaque that had already formed akin to Drano removing scale and rust from pipes. The best we have so far is statins like Lipitor and Crestor, which has been shown to diminish plaque burden by Intravascular Ultrasound or as it is known IVUS. The mechanism by which statins work is believed to be more reorganization of plaque than the removal of material.
In June 2003 a study was published in JAMA 2003, which electrified the field of cardiology. Here was the promise fulfilled, a substance that would remove plaque. That substance is ApoA-1 Milano now called ETC-216 as it was purchased by Esperion and renamed.
Over the time period November2001 and March 2003, 123 participated in the study. All had ACS- acute coronary syndrome and I have blogged about this syndrome frequently. They were randomized into three groups’ placebo, low-dose and high-dose, and underwent once a week infusions of Apo for five weeks. IVUS was done before and after, and then analyzed to see the differences in plaque volume and composition.
The mean percent decrease was 1.06% in the treatment group and an increase of .14% in the control group. The absolute reduction in atheroma volume was 4.2% and this carried a p value of <.001. The lower the p value the more significant thus this is a very significant result.
In the short span of five weeks, atherosclerotic coronary lesions were shown to reverse. Further, the dose of ApoA-1 did not matter. Both the low-dose and high-dose had the same effect and it is believed that the mechanism of action is the stimulation of reverse cholesterol transport.
That’s were it ended. Since 2003 no further work was done because Esperion was purchased by Pfizer and Pfizer was probably doing that to “bury” it because it was working on its blockbuster oral drug torcetrapib. That failed and Pfizer said adios to cardiac research.
The Medicines Company has a track record of delivering new drugs to market that have not been adequately studied. Let’s hope that the work will now be started and finished to show whether this compound is the beginning of a new treatment strategy for atherosclerosis. I will keep you informed.
To Clot or not to Clot
A recent blog discussed the fact that clots cause myocardial syndromes. Stable clots induce STEMI and unstable or waxing and waning clots cause ACS or acute coronary syndrome. The differences between the unstable and stable clots are not fully understood but much of the difference is due to platelet activation and much of that activation is due to smoking.The question has now become why do the clots form? What does the inside of the artery look like and can these changes be predicted and prevented. I have blogged before that a large portion perhaps up to 40% of myocardial infarctions is not caused by severely diseased arteries. What I mean is the extent of blockage in these arteries is less than 50% of the lumen. It was believed that the arteries in the less severe disease states suffered from edge “cracking”. When the normal artery meets the abnormal plaque a fragile zone is created and under the right circumstances ruptures. This micro crack exposes the blood to abnormal components and the clotting cascade starts.
A well known phenomenon is that an individual with acute coronary syndrome will often have several plaques that look “angry” at cath and it can be difficult to know exactly which one to fix.
Dr. Renu Virmani is a cardiac pathologist and has spent her life looking at coronary arteries that have caused syndromes and death. Unfortunately, if she is looking at someone’s coronary arteries that patient has died from their problem. Someone kindly consented for an autopsy. This work has been invaluable in the everyday practice of cardiology as it has allowed us to learn and modify our techniques. She was among the first to recognize and characterize late stent thrombosis and to give us an understanding of the incomplete reendothelialization that occurs with drug stents and to help us understand that longer use of Plavix is warranted.
Published in J Am Coll Cardiol 2009;DOI:10.1016 a new study again points to our continued learning about the relationships of thrombus to plaque morphology.
Next…what we learned.
New Study on Viral Protein Therapy for Acute Coronary Syndrome
Acute Coronary Syndrome, or as it is better known ACS, is the transition point to full blown myocardial infarction. It is a syndrome of waxing and waning chest discomfort and it is marked by changes in the ECG that also comes and go. It is also marked by positive cardiac enzymes, but usually not to the extent of an STEMI- ST elevation myocardial infacrtion or NSTEMI- non ST elevation myocardial infarction. The ST stands for a segment of the ECG- electrocardiogram- that deviates depending on blood flow to the heart.
I have spent the last 20 years working on various drugs to prevent ACS or delay its progression to full blown myocardial infarction. We as a discipline have come a long way since the days of heparin and much prayer. Now the first study of a viral protein for therapy of this syndrome has been presented.
Presented at the Canadian Cardiovascular Congress 2009 in October, this study postulated that a viral serine protease inhibitor VT-111, which reduces the migration of a type of blood cell known as a monocyte to sites of vascular damage might work in ACS.
The lead investigator is Dr. Tardif of the Montreal Heart Institute, which is a prestigious site of many groundbreaking studies. It used 48 patients and found that compared to placebo a significant dose dependent reduction in cardiac troponin was associated with VT-111 at all data points. No difference was seen in key safety measures.
This study will now hopefully move on to larger scale trials and will possibly become another tool in our war chest of agents to halt this syndrome. It is another example of how we are moving away from chemical compounds to cell based therapy and viral protein therapy. It is an exciting possibility. I will keep you informed of its progress.
About the Institute
Browse by Category
- Acute Coronary Syndrome (14)
- Adult Stem / Cell Treatment (10)
- Angioplasty (4)
- Aortic Aneurysms /Stents / Grafts (13)
- Atherosclerotic Heart Disease (12)
- Atrial Fibrillation (11)
- Cardiac Imaging (4)
- Cardiac Surgery (19)
- Carotid Disease (7)
- Cholesterol (53)
- Chronic Angina (13)
- Clinical trials (3)
- Coronary Artery Disease (34)
- diabetes (15)
- Heart Failure (30)
- High Blood Pressure (22)
- Myocardial Infarction (36)
- Pacemaker / AICDs (9)
- Peripheral Artery Disease (5)