Mircea CINTEZA

Since decenies, the main place in chronic anticoagulation (AC) is occupied by antivitamin K drugs (AVK), mainly warfarin. The development of low weight molecular heparins or new antiplatelet drugs did not change the situation.

In the last few years a new group of oral anticoagulants emerged in clinical practice. Their efficacy and safety seems to be so good, that they entered very quickly in guidelines (1,2), situation not often encountered in clinical medicine.

AVK have a very important limit: lack of adherence to long therm therapy. It is considered that only about 20% of patients with nonvalvular atrial fibrillation (AF) who started anticoagulation with AVK and have good indication to do so chronically remain on this therapy. The remainig 80% are in consequence in great danger. If the titration is not well performed or it is not performed at all, the main consequent risk is either of hemorrage or of thrombo-embolic events. Other important limit is the large interferrence of AVK efficacy with concomitant administration of a large group of other drugs, as well as a strong influence of diet in the same respect.

Of course, AVK therapy has also good qualities.If well monitored, this therapy may adapt very well to difficult clinical conditions, like renal insufficiency or in aged persons. It may be used in some conditions, such as chronic therapy for valvular prostheses, where new anticoagulants have not yet an indication. They may be associated in well defined clinical conditions with antiplatelet therapy, which is not allowed to date for the new AC drugs. They have a good antidot, vitamin K. Last, but not least their cost is small at first glance.

The new drugs aproved to be used in some clinical conditions are: Dabigatran, which is a direct antithrombinic agent and Rivaroxaban and Apixaban, as inhibitors of the Xa factor. Other drugs were tested on humans, but to date are not used for different reasons: Ximelagatran, withdrawn in 2006 because of hepatic toxicity, Edoxaban, Betrixaban or Darexaban, which do not have yet a final destiny in clinical medicine (3).

To date, the clinical trials dedicated to different conditions include several tens of thousands of patients, beeing one of the largest cathegory of clinical trials (3-6). The first indications approved were the prevention of the venous thromboembolism, followed soon by the therapy of the deep venous thrombosis and pulmonary embolism (1,3,5). A large field of interest was the anticoagulant therapy in atrial fibrillation (2,4,6). All the three drugs are approved or ready to be approved either in the USA and Europe to be used in this domain.

Another field of interest is the use of the new drugs in acute cotonary syndromes (7). The exact place of this therapy in this field is not yet defined. We have to mention that their concomitant use with antiplatelet therapy is not defined as well (7).

The great advantage of the new oral AC drugs is their huge potential to have best adherence for a long therm therapy, because they do not have to be monitored.Most of the studies showed that they are efficent and secure in their effect, being at least non-inferior to warfarin and sometimes, even superior in therms of less number of severe side effects. They seem to be little influenced by other concomitant therapy or diet, but some authors still suggest concern in this respect (6). In a word, they are efficient, secure, stable and easy to be administred.

These advantages may generate by themselves some potential week points. We base our trust on their efficacy and security on a statistical base (the mean good result in clinical trials). However, would we be more secure to have the possibility to monitore their efficacy in the individual patient in front of us, how we use to do with AVK drugs ? To date, such a test simmilar to the INR (International Normalized Ratio) to monitore the instant anticoagulant power is not available. It seems to be on research, as it is the search for an efficient and low cost antidote (6).

Another problem is the cost, high as usual for new and good drugs. Of course, in time the cost of these drugs could decrease. But even now, if for AVK drugs we consider the cost of the infrastructure to monitore the therapy, as well as as the cost of the time dedicated to that medical visit, the total costs of AVK therapy or the cost of a new oral AC therapy could be comparable.

It is to be mentioned that the knowledge in the field of new AC is still changing, as it would be expected. Some recent review of the literature consider, for instance, thet the bleeding risk of such therapy is greater than intially considered (8).

In conclusion, we face a moment of clear progress in cardiovascular therapy, comparable with the great moments of the last half a century, the introduction of ACE inhibitors, statins, sartans, fibrinolytics, new antiplatelet drugs and others. Let us hope that the final impact of the new anticoagulants will be even greater than presumed today.

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Mircea CINTEZA

A paradigm accompanies coronary artery pathology since decenies now: which is our main argument used when taking the decision how to make treatment ? This argument is the presence of ischemia.

The 70% stenosis or more is the most useful parameter. But why exactly 70%? Because starting from this point ischemia is generally presented. But not always. Than we may use the flow reserve. In practice is not used very often, because is costly.

It is indicated sometimes to search ischemia by different methods. The ECG stress test has its limits, especially for sensitivity. Scintigraphic perfusion scan and echocardiography are costly (the first) or operator dependent and time consuming (the second).

It is logical to look for viable myocardium by different methods, but this is applicable only when heart failure accompanies coronary artery disease. Most of the coronary patients don’t have heart failure.

But now comes the main question: is our main goal to treat chronic ischemia ? Most of the heart attacks come not because a severe stenosis is completing its progressive evolution, but because the plaque ruptures or becomes unstable and favors the development of an occlusive thrombus.

So, a patient with coronary arteries diseased may have or have not chronic ischemia. But for sure they are in danger of making acute ischemia when a thrombus adds to an existing plaque. And the main goal of therapy is not to treat chronic ischemia, but to treat or to prevent the acute thrombotic coronary phenomenon.

But the acute phenomenon has (almost) nothing to do with the previous presence of ischemia. Nobody demonstrated that at 70%, 80% and 90% stenosis are accompanied linearly or exponentially by a heart attack in the near future and the 60% stenoses are not (or significantly less often).

On the contrary: many pathological studies demonstrate that the ruptured or the unstable plaques originate mostly from less occlusive plaques, but with a soft composition which is unstable and may promote thrombogenesis.

Than why do not we use the diagnosis of an unstable plaque as the main argument to intervene promptly, instead to search for a significant stenosis? Because for the moment we do not know to identify with accuracy unstable plaques ant therefore we use the surrogate end point of ischemia produced by a significant stenosis.

We may notice from this point of view that revascularization by interventional cardiology is an incomplete term. When implanting a stent, the plaque bellow is much more stabilized than before in most cases. If a restenosis occurs, this is done by a proliferative material much more stable than the original atherosclerotic plaque. We may say that by doing PTCA with stent we revascularize AND stabilize the atherosclerotic coronary.

So, our main indicator to intervene should be the instability of the coronary plaque. Can we identify it today?

Not yet, but in this direction progress is remarkable. In an excellent editorial in this issue of the Journal (1) Viviana Aursulesei makes a very good synthesis of the methods used currently in clinical research to identify the unstable plaque. Some methods seem now to be familiar to clinicians: intravascular ultrasound with virtual histology, high resolution magnetic resonance imaging, positron emission tomography and even optical coherence tomography have results in identifying unstable plaques presented at general cardiology meetings and journals. Other methods, like palpografia, the elastogram or the modulogram of the plaque (1) are methods only known by a limited number of specialists.

The results of these methods are analyzed now in clinical trials with clinical outcome endpoints. The information given by the new methods are included in new risk factor charts to complete the traditional ones we use today. The accuracy of the new methods to predict acute events is profoundly analyzed.

The ability of the new indicators to predict coronary outcome is still the weak point. The sensibility and specificity of any of the new methods does not yet overcome the traditional way to predict bad outcome in coronary artery disease. Everything seems logical in the new parameters – however something is still missing to bring them in the pole position.

„Most likely, a multimarker strategy that includes risk factors, molecular and genetic biomarkers, noninvasive imaging markers, will be a truly viable option in terms of practice” – comments Dr. Aursulesei in her editorial and I totally agree.

Looking for ischemia instead of looking for the potential instability of a plaque seems to me to be a historical error of cardiology, assumed consciously until the moment when we will be capable to identify correctly the unstable plaque. Ischemia should stay in that moment as the second main endpoint of coronary disease therapy.

The presence of a potential unstable plaque is the real argument that we should be promptly aggressive in the therapy of coronary artery disease.

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Mircea CINTEZA

   Most of the doctors who practice medicine today learned during their medical school that heart failure is an irreversible disease, with irreversible structural changes, with a prognostic identic with cancer and a 2-year- survival in cases with deffinite diagnosis. Irreversibility is given by a pathologic remodeling of the ventricle, due to cardiac overload or injury combined with neurohormonal activation.
   Different causes lead to pathologic cardiac remodeling in common ways (1). There are 3 main models of remodeling: concentric ventricular remodeling in pressure overload, eccentric hypertrophy with dilation in volume overload and a mixed model after myocardial infarction. The initial phase of the model may be adaptative, but soon the maladaptative model appears and progresses till the terminal phase of heart failure. There are no clinical or biohumoral data to define the moment of progression from the adaptative to the maladaptative phase (1)
   The main structure involved is the myocyte, but surrounded by fibroblasts, collagen, other components of the interstium and vasculature. Local delivered hormones, like angiotensine, norepinephrine or endothelin contribute to myocyte hypertrophy, myocyte rarefaction and development of fibrosis. The hypertrophied myocytes are not functionally more competent, they are fewer than the former physiologic number of myocytes and they continue to deteriorate in the conditon of a bad neurohormonal and larger fibrosis ambient. Sometimes, in heart failure, a permanent release of small amounts of troponins does exist in the absence of ischemia (1), showing that myocyte deterioration is continuous in heart failure. In these conditions the irreversibility of the myocardial deterioration in heart failure seems to be demonstrated, as well clinically and pathologically.
   And – surprise! More and more data appeared that in some conditions – mainly after prolonged mechanical support of the failing heart, but also after sustained therapy with beta-blockers or angiotensin converting enzyme inhibitors (ACEIs) – signs of pathological reversibility were demonstrated. In these cases clinical improvement appeared on a medium term, even in the condition of stopping the mechanical support. Thus, the concept of reverse remodeling developed. The term was introduced by Kass in 1995 and revised by the author and Koitabashi in 2012 (2).
   The first problem is to recognise the phenomenon. Functional data are useful. Reduction in end-systolic volume or preserving the same endsystolic volume having a smaller enddiastolic volume denotes better efficacy of the failing ventricule. But this has to be preserved for a longer period. There are also histologic feaures that have to be demonstrated: reduced myocyte size, reduction of interstitial fibrosis, increased capillary density, improved beta-adrenergic response, improved calcium handling or SERCA2 gene upregulation (2,3). These parameters are more difficult to demonstrate in the clinical follow up.
   The second observation is that not all therapies of heart failure succeeded to show elements of reverse remodeling. Mechanical support does this the best: left ventricular (LV) assist devices, biventricular pacing, resinchronization or diastolic containement devices (2,3). Beta-blockers, ACEIs and mineralocorticoid receptor inhibitors have positive proves. On the contrary, calcium antagonists, renin or Tumor Necrosis Factor inhibitors, endothelin antagonists or statins had no positive results (2).
   There are some encouraging results with stem cell therapy. However, here is a long way to progress, starting with the source of stem cells, continuing the way of injection, the way to stabilize them in the myocardial tissue and finally to make them differentate in functional cells (2,3). Each of these steps are today under intense investigation.
   The results of today show that only about one third of patients with defined heart failure due to different ethiologies have signs of reverse remodeling with sustained appropriate therapy, either mechanical, with drugs or stemm cells. The prognosis in those cu show reverese remodeling is much better than in those who do not present such signs (4).
   There are different other ways imagined to develop a better response of the failing myocardium: inhibition of GMP-specific 3’,5’-cyclic phosphodiesterase 5, upregulation of endoplasmic/ sarcoplasmic calcium ATPase 2, calcium-sensor protein S100 A1 and other, all tested clinically (2). The solutions not yet tested in man are even more numerous.
   Reverse remodeling is a very important goal and hope in the therapy of congestive heart failure. Crucial questions have to be solved in this direction (5):

• different etiologies of heart failure respond differently to reverse remodeling therapies?
• Should we have better methods clinically available to monitor the appearance and progression of reverse remodeling?
• should we use different therapies for different subgroups of patients?

   For the moment, we may conclude with Eugene Braunwald, citing Winston Churchill (3):
“Now, this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning”.

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