Antidote for Dabigatran

Until recently, warfarin (also known as Coumadin), a vitamin K antagonist (VKA), had been the only available oral anticoagulant. The use of warfarin has been always complicated by many issues including its narrow therapeutic index and multiple drug and diet interactions affected its safety, compliance, and efficacy. Patients needed regular and close monitoring of the its anticoagulant effect (how thin is blood?). Despite regular monitoring, patients suffered bleeding complications when blood was too thin (supra-therapeutic range) or blood was thin within the desired range but other patient factors (such as trauma/injury) resulted in bleeding.

A very common use of warfarin is for anticoagulation in patients who suffer from atrial fibrillation. With increasing age, the risk of atrial fibrillation increases and atrial fibrillation is common older individuals. Patients with atrial fibrillation can develop a clot in the left atrium of the heart and this clot can dislodge and go to other parts of the body. If this dislodged clot goes to arteries that supply blood to the brain, it usually results in large stroke. The risk of stroke with atrial fibrillation varies from person to person but can be calculated using a CHADS2 score and may vary from 1.8% per year to 18% per year without anticoagulation.

The above noted problems with warfarin prompted the development of new oral anticoagulants that target key coagulation proteins. Within past few years, FDA has approved several new oral anticoagulants that don’t require regular monitoring with blood tests and have very few drug interactions. However, one limitation with these new anticoagulants is lack of an antidote that can quickly reverse the effect of these drugs in cases of emergency, such as when a patient is bleeding. On the other hand, vitamin K can be used to reverse the effect of warfarin. Several pharmaceutical companies and other research groups are trying to develop agents that can effectively reverse the effects of these new anticoagulants.

Pollack and colleagues have published in this issue of the New England Journal of Medicine a trial of such an antidote of dabigatran, an oral thrombin inhibitor that is approved for the prevention of stroke in patients with non-valvular atrial fibrillation and for the prevention and treatment of venous thromboembolism. Investigators used idarucizumab, a monoclonal antibody fragment that binds dabigatran with an affinity that is 350 times as high as that of dabigatran’s affinity with thrombin (a coagulant protein through which dabigatran acts). In blood, idarucizumab binds free and thrombin-bound dabigatran and neutralizes its activity. In this prospective cohort study, investigators examined the safety of 5 g of intravenous idarucizumab and its inhibitory effect on dabigatran in patients who had serious bleeding (group A) or who required an urgent procedure (group B). Investigators determined the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab (primary endpoint).

Of the 90 patients who received idarucizumab (51 patients in group A and 39 in group B), idarucizumab normalized the blood coagulation in 88 to 98% of the patients often within minutes. Concentrations of unbound dabigatran was below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, bleeding was controlled at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.

As noted above idarucizumab is specific for dabigatran and is unlikely to be effective with other new oral antocagulants. However, various reversal agents and/or strategies, nonspecific to dabigatran, are available to physicians, including prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa.

Southern Dietary Pattern and Heart Disease

We are what we eat – and the diseases we get are the often (at least partly) a result of dietary choices we make.

A study published in the American Heart Association’s journal, Circulation, finds that people who have Southern dietary pattern – characterized by added fats, fried food, eggs, organ and processed meats, and sugar-sweetened beverages – are at a higher risk of heart attacks and sudden cardiac death. Investigators analyzed data from 17,418 participants in Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national, population-based, longitudinal study of white and black adults aged ≥45 years, enrolled from 2003-2007. They found 56% higher risk of heart attacks and sudden cardiac death among individuals who eat ‘Southern’ food than those who rarely eat such food.

So next time when you are thinking about what to eat, chose something healthy!

Updated Guidelines - Diabetics and Cardiovascular Disease

American Heart Association and American Diabetes Association has recently published an update to the guidelines for the prevention of cardiovascular disease in adults with type 2 diabetes mellitus. There are certain interesting aspects to it.

1. Use of Hemoglobin A_1C for the diagnosis of diabetes mellitus
 Pre-diabetes = A_1C between 5.7% and 6.4%
Diabetes Mellitus = A_1C >/= 6.5%

2. Lifestyle Management of Diabetes
Physical Activity
Nutrition
Weight Reduction (through physical activity, nutrition, weight-loss drugs, and/or bariatric surgery)

3. Cardiovascular risk reduction
Control of blood glucose (A_1C <7%)
Control of blood pressure (< 140/90)
Control of Cholesterol (statins)
Aspirin for moderate 10-year CVD risk (5-10%)

4. Screening for cardiovascular diseases in asymptomatic patients
Paucity of data suggesting any specific benefits of invasive interventions over medical therapy alone makes any CAD screening in the asymptomatic patient with diabetes mellitus highly controversial.

Statins After Stroke: What is the effect on mortality and morbidity?

Statins (cholesterol lowering drugs such as Lipitor or Crestor and others) have been shown to reduce major cardiovascular events after stroke and are considered the standard of therapy in patients with stroke. Most patients with new stroke are prescribed one of the statins when discharged from hospital. However, whether the beneficial effects of statins seen in strict clinical trials settings are also present in non-clinical trial settings remains to be seen. In other words, while it is established that statins have efficacy (work in clinical trials) it remains to be seen whether statin have effectiveness (work in usual delivery of healthcare).

The distinction between efficacy and effectiveness is an important one. A clinical trial has inclusion (and exclusion) criteria which limit enrollment to only a certain group of individuals. Patients who volunteer for clinical trials are also known to be more compliant and receptive to medical advice. Furthermore, patients in clinical trial are closely followed (and observed) and, therefore, perhaps get better care. Thus, results seen in a clinical trial setting may not hold true in the usual healthcare delivery environment where all sort of patients get drugs (or interventions), compliance may be an issue, and patients are not as closely followed. This necessitates effectiveness studies, which are not commonly performed, although thought to be quite important. Perhaps the biggest reason is that such studies are not required for a drug approval by FDA and perhaps drug companies fear that effectiveness studies may show that a particular drug (or intervention) is not as effective as shown in the clinical trial (or not effective at all).

It is then no surprise that effectiveness studies for statins in stroke (one of the commonly prescribed drug class) have not been done, that is until now. O’Brien et al report in this issue of circulation such an effectiveness study. Investigators linked data from Get With The Guidelines (GWTG)-Stroke register with the Medicare data and followed patients 2-year post-discharge for major cardiovascular events, time spent at home (out of hospital or nursing home), all cause mortality, readmissions to hospitals, and hemorrhagic stroke. Investigators report that from 2007–2011, 77,468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke. Of these 77K patients, 71% were discharged on some form of statin therapy; 31% on high-intensity statin therapy.

What they found was that the rates were lower for major adverse cardiovascular events (9% lower), mortality (16% lower), and readmission (7% lower) within two years of hospital discharge were lower for patients who were taking statins as compared with those not taking a statin. On average, patients also spent 28 more days at home. Of note, these results were adjusted for risk factors. There were no differences in rates of hemorrhagic stroke, ischemic stroke, or cardiovascular readmission by statin therapy.

Now contrast this data with the results from clinical trials of statins that showed a 20% reduction in major adverse cardiovascular events, 16% reduction in risk of ischemic stroke, and as high as 32% reduced risk of mortality. Obviously, as expected, the benefits are much larger in a clinical trial setting. This example, among others, highlights the need for effectiveness trials. Of note, this trial was funded through PCORI (a tax-payer funded program) and not by a drug company.

Life Expectancy After Myocardial Infarction

This study examines sex and race differences in long-term survival after AMI using life expectancy and YPLL to account for differences in population-based life expectancy. Investigators used the Cooperative Cardiovascular Project, a prospective cohort study of Medicare beneficiaries hospitalized for AMI between 1994 and 1995 (N = 146,743).

Investigators found that the life expectancy estimates after myocardial infarction were similar for men and women of the same race but lower for black patients than white patients.

Below is a figure from the manuscript summarizing the findings