De Caterina R

Genetic determinants of response to vitamin K antagonists

The narrow therapeutic index, the large interindividual variability, and the severity of adverse drug reactions connected with vitamin K antagonists, together with their ample use in medical therapy, have prompted the search for strategies to better assist doctors in the choice of the safest and most effective dose of these drugs. The molecular mechanism by which oral anticoagulants exert their effect is an interference with the bioactivation of vitamin K. This mechanism is therefore the subject of numerous pharmacogenetic studies, aimed at finding the relationship between genetic variants influencing the metabolism or action of the drug and therapeutic outcomes. However, genes involved in the metabolism or action of vitamin K antagonists are many, and the role of some of them has not yet been fully understood. In this review we present and discuss current knowledge about the relationship between genotypes and the development of adverse drug reactions, focusing on gene variants that appear to influence dosing and clinical endpoints, and aiming at clarifying the usefulness of pharmacogenetic approaches as applied to this treatment.

Italian intersocietary consensus document on aspirin therapy in primary cardiovascular prevention

The indications for the use of aspirin in primary cardiovascular prevention continue to be a source of intense debate, with major international guidelines providing conflicting advices. This document, written by delegates of the main Italian scientific societies dealing with cardiovascular prevention and modeled on a similar document by the European Society of Cardiology Working Group on Thrombosis, reviews the evidence in favor and against the use of aspirin therapy in primary prevention based on data cumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, this document argues for a pragmatic approach to the use of low-dose aspirin in primary cardiovascular prevention, and suggests its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding.

[Ranolazine in the prevention of anthracycline-related cardiotoxicity].

Anthracyclines rank among the most effective anticancer drugs. They may however cause a dose-dependent and cumulative cardiotoxicity, eventually leading to heart failure. The antitumoral cytotoxicity of anthracyclines and their cardiotoxicity are believed to be due to different mechanisms, and there is therefore an active search for developing drugs able to protect the heart without impairing their chemotherapeutic efficacy. The foremost hypothesis explaining cardiotoxicity is the anthracycline-dependent production of reactive oxygen species (ROS). A ROS-induced calcium (Ca 2+)-calmodulin-dependent protein kinase II (CaMKII) hyperactivity can cause diastolic Ca2+ overload secondary to the activation of the late sodium (Na+) current (INaL). Furthermore, INaL hyperactivation can initiate a vicious cycle leading to sustained oxidative stress and energetic stress, with serious ATP depletion, similar to that occurring after the exposure of hearts or isolated cardiomyocytes exposed to anthracyclines. We hypothesize that anthracyclines may cause, through a ROS-dependent CaMKII hyperactivation, increased INaL, leading to a vicious cycle that worsens the redox imbalance with resulting mechanical and electrophysiological dysfunction and heart failure. In this light, we here review the molecular and clinical characteristics of ranolazine, the most powerful and selective clinical inhibitor of INaL, and speculate on the possibility that it may be used as an effective drug protecting against anthracycline-related cardiotoxicity.

[Pharmacogenetic algorithms for predicting the appropriate dose of vitamin K antagonists: are they still useful?].

The severity of side effects that may occur with vitamin K antagonists due to their narrow therapeutic window requires great attention in finding out the most appropriate dose for these drugs. Pharmacogenetic research has now considerably helped clarifying the relationships between genetic variants and sensitivity to such therapy, paving the ground to predictive algorithms that include clinical and genetic variables to establish the best doses to start and maintain an adequate anticoagulation. Pharmacogenetic algorithms indeed aim at identifying tailored regimens, reducing adverse drug reactions and subsequent hospitalizations, optimizing therapeutic efficacy and containing costs. Here we describe the results so far achieved in pharmacogenetic research with vitamin K antagonists, analyzing studies that have assessed the usefulness of such algorithms.

[Management of thromboembolic risk in patients with atrial fibrillation in Italy: baseline data from the PREFER in AF European Registry].

BACKGROUND Atrial fibrillation (AF) is a common heart rhythm disorder associated with an increased risk of stroke, heart failure and death. Although available evidence supports the administration of oral anticoagulants with respect to other treatment options to prevent thromboembolism, the use of oral anticoagulation therapy remains suboptimal. The PREFER in AF registry was conducted to evaluate patterns of prescriptions and patient adherence to guidelines, clinical features, quality of life and treatment satisfaction. METHODS The PREFER in AF registry enrolled consecutive patients with AF recruited in high-volume cardiology centers, with AF documented during the previous 12 months. Patients were assessed at baseline and at 1-year follow-up. The present report provides Italian baseline data compared with data from other European countries participating in the registry. RESULTS The registry enrolled 1888 Italian patients (out of 7243 in Europe), with an average age of 70.9 years. Main comorbidities included hypertension (73.5%), dyslipidemia (38.7%) and obesity (21.9%). The risk of thromboembolism was assessed using the CHA2DS2-VASc score, according to which only 4.7% of Italian patients scored 0, whereas 11.3% scored 1 and 84% scored ≥2. Italy is the Western European country with the lowest use of vitamin K antagonists (71.6%; average rate in Europe: 78.3%) and the highest average INR measurements, whereas time in therapeutic range is 72.2%, lower than in any other Western European country with the exception of Spain. Most Italian patients are unsatisfied with treatment, and only 36% report no difficulties in taking anticoagulation therapy compared with 70.3% of patients in other Western European countries. CONCLUSIONS Among Western European countries included in the registry, Italy has the lowest prescription rate of vitamin K antagonists and the highest rate of INR measurements. Italian patients also report lower levels of satisfaction with treatment and a higher subjective difficulty in managing anticoagulation therapy. The new oral anticoagulants may favor treatment management, thus having the potential of improving medication adherence and persistence as well as quality of life.

[Aspirin in primary prevention of cardiovascular diseases: how to balance risks and benefits].

While the use of aspirin in the secondary prevention of cardiovascular atherothrombotic disease is well established, many aspects of primary prevention are still unclear. Uncertainties mostly depend on a doubtful riskbenefit ratio, because of the low atherothrombotic risk of populations involved on the one hand, and the nonnegligible bleeding risk of treatment on the other. Areas of specific doubt are those of diabetes and asymptomatic peripheral arterial disease, where neither single trials nor meta-analyses allow issuing high-grade specific recommendations at the moment. The present review aims at giving an account on this topic, highlighting areas for further studies, but also attempting at providing a rationale for what to do practically now, while awaiting more conclusive evidence.

[Angina with normal coronary arteries: a common but often neglected association].

The angiographic evidence of normal coronary arteries or moderate coronary artery disease is a relatively common finding in patients with a history of angina, with a higher prevalence in females. This condition is not a single pathological entity, but comprises several different presentations, such as cardiac syndrome X, vasospastic angina, myocardial bridges, as well as coronary alterations with more doubtful clinical implications, such as serial moderate coronary artery lesions or focal coronary dilations. These pathological conditions are different in pathophysiology, management, and prognosis, and for this reason their correct diagnostic definition, beyond the angiographic evidence of normal coronary arteries, appears mandatory. This review aims at providing an update in the conundrum of entities comprising angina with normal coronary arteries, and at explaining different diagnostic and therapeutic approaches.

Dabigatran as an alternative to warfarin for the prevention of thromboembolism in atrial fibrillation

Atrial fibrillation (AF) is an independent major risk factor for stroke, and antithrombotic therapy is here recommended according to stratification of the patients thromboembolic and hemorrhagic risks. Recent evidence is leading to the replacement of vitamin K antagonists, the efficacy of which in preventing stroke in AF is well established, with better tolerated and more manageable new anticoagulant drugs, with a lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments. Among new anticoagulants, dabigatran etexilate is a direct, competitive inhibitor of thrombin. It was evaluated for patients with AF in the RE-LY trial, showing lower rates of stroke and systemic embolism at a dose of 150 mg twice daily with similar rates of major hemorrhage compared with warfarin; and non-inferiority compared with warfarin for the prevention of stroke and systemic embolism at a dose of 110 mg twice daily, with lower rates of major bleeding. Beside dabigatran, oral factor Xa inhibitors are also emerging for the prevention of thromboembolic events in AF. Despite the obvious advantages of these new oral anticoagulants over vitamin K antagonists, further information is still needed on how to prioritize the patients deriving the greatest benefit from these novel agents on the basis of patient characteristics or drug pharmacokinetics. There is also a need for assessing their long-term efficacy and safety over decades in the real-world setting.

Inibitori di pompa protonica e clopidogrel: un'associazione da evitare?

: Dual antiplatelet therapy with aspirin and clopidogrel reduces cardiovascular events following an acute coronary syndrome or stent implantation, but the associated increased risk of gastrointestinal bleeding often leads clinicians to the co-administration of proton pump inhibitors (PPIs). PPIs have been shown to decrease antiplatelet effects of clopidogrel ex vivo, raising doubts on the safety of this drug combination. Clinical trials investigating PPI-clopidogrel interaction have provided conflicting results and have been often criticized. Moreover, a prospective, double-bind, randomized, placebo-controlled study conducted with adequate follow-up and sample size has not yet been performed. Indeed, the COGENT trial, which would have had such characteristics, has been stopped prematurely. The question is therefore still unresolved, and clinical effects of PPI-clopidogrel interaction cannot be excluded. As a practical consequence, this combination therapy is recommended only for patients at high risk of bleeding (prior upper gastrointestinal bleeding, advanced age, concomitant use of warfarin, steroidal or non-steroidal anti-inflammatory drugs and Helicobacter pylori infection), avoiding in any case PPIs with greater affinity for CYP2C19, such as omeprazole and esomeprazole.