Introduction
In 1996 the ISCOAT study was published in The Lancet [
1] focused on management and bleeding complications associated with chronic anticoagulation with vitamin K antagonists (VKA); the results regarding thrombotic complications were published in the subsequent year [
2]. To our knowledge, the ISCOAT study was at that time one of the first studies on patients treated with VKA anticoagulation designed and performed according to rigorous methodological criteria. It was a large, prospective, observational, multicenter, inception cohort study on the real-life management of VKA-treated patients who were monitored by means of the INR system (established in 1985 [
3]) in dedicated anticoagulation clinics belonging to the Italian Federation of Anticoagulation Clinics (FCSA). After 20 years, VKA are still the most widely used anticoagulant drugs in the world. It is fair to surmise, however, that many aspects relating to their use and clinical results may now be changed.
In the present study, we aim at assessing the characteristics of naïve patients who started VKA-anticoagulation, and were monitored in FCSA centers participating in the FCSA-START-Register, and clinical results achieved during follow-up. We also compare the currently observed results with those of the ISCOAT study published 20 years ago.
Discussion
The present study shows that patients treated with VKA in Italian anticoagulation clinics present very good clinical results, as demonstrated by the particularly low rates of complications, both hemorrhagic and thrombotic. It also shows that important changes have occurred over the last 20 years in patients treated with VKA, and in their management in our country. This is especially the case as regards the composition of the treated populations, the indications for anticoagulation, and in a marked reduction of thrombotic complications during treatment.
The global rate of major bleeding of 1.38% per year recorded in the present study compares well with the rates of 1.40–3.40% per year reported in a recent meta-analysis of randomized clinical trials in patients with AF [
13], and the 1.2–2.2% per year observed in trials on direct oral anticoagulants versus standard therapy (LMWH + warfarin) in patients with VTE [
14,
15]. Higher rates of major bleeding have been reported in recent population studies: 3.8% per year in a Canadian population-based cohort study [
16], and of 2.24% per year in a report from the Swedish register Auricula [
17]. There is a relatively low rate of major GI bleeding in our cohort, especially in comparison with that of intracranial events. Some potential explanations may be advocated for these results. First, differently than for intracranial bleeding that is always categorized as a major event, the classification of GI bleeding is not always the same in all the reports; in our study we define them as major only in relation to the blood losses or transfused units. This is why some GI bleeds are reported as NMCRB, and some minor GI bleeds (such as proctorrhagia) were not considered even as NMCRB. Second, the very high prevalence of elderly people with AF in our cohort is likely the reason for the relatively high rate of intracranial hemorrhages; whereas, the large use of drugs for gastric protection in very elderly patients treated with VKAs may be a reason for the relatively low rate of GI bleeding. The rate of NMCRB recorded in our cohort is rather low (1.62% annually). It cannot be excluded that this low rate is, at least in part, due to underreporting. It should be pointed out, however, that the completeness of the imputed data was constantly controlled by the monitor of the registry, who also read all the information added to the electronic database by the treating doctors. It is difficult to compare our result with others in the literature since in some cases this information is not reported, or the criteria adopted for classifications are different. When reported directly, or derivable from the data shown, the rates of NMCRB in the warfarin treated patients included in phase III trials on direct oral anticoagulants in AF or VTE patients vary largely: from 2.2% [
18] to 11.4% [
19].
As regards thrombotic complications, the rate of 0.53% per year (0.67 and 0.46% in VTE and AF patients, respectively) recorded in our study is particularly low when compared with 1.66% per year calculated in a meta-analysis of trials on patients with AF [
20], or with 2.2% per year reported in trials on VTE-patients [
21], or with that of 2.65% per year found in the Auricula registry [
17]. The lower rates of both bleeding and thrombotic complications recorded in our study in comparison with the Auricula’s results are surprising and not easy to explain, especially because both studies include patients managed in anticoagulation clinics, with similar classification of clinical outcomes. What is more, the mean Auricula TTR is higher (76.5%) than that in our study (66.0%), a rate which is, however, within the range of 65–70% recommended for ensuring high quality of anticoagulant therapy [
22]. TTR is considered a valuable tool to assess the quality of anticoagulation control which, in turn, is important to determine clinical outcomes of treated patients [
23,
24]. However, recent studies fail to find a correlation between TTR and complications (at least thromboembolic) [
25]. TTR results are influenced by many factors, such as geography [
24], study settings (community practice, anticoagulation clinics or clinical trials) [
26], patient characteristics [
27], presence of co-morbidities [
28], and time-period since start of treatment [
29,
30]. In a large North-American retrospective cohort study on patients treated for AF the mean TTR is 53.7% overall, but it improved over time, increasing from 47.6% for patients with <6 months of therapy to 57.5% for those with ≥6 months of testing (
p < 0.01) [
30]. Since, unlike the Auricula registry, our study includes only patients who started VKA-treatment and who, therefore, had shorter treatment times, this factor may well be one potential reason for the lower TTR rate recorded in our study.
We compared the results of the current study with those obtained in the original ISCOAT study [
1,
2] (Table
4). The two studies had the same design and the same intended patient population that started VKA treatment and was managed by anticoagulation clinics affiliated with FCSA. While some results remain substantially similar between the two studies, there are big differences in other respects. The treated population in the present study is significantly older (on average 10 years more,
p < 0.01), with the proportion of patients aged >80 years up from 8% to more than 28%. This important change is associated with the sharp increase in patients treated for AF (<17% 20 years ago and now >61%). Whereas other indications, such as VTE and heart valve prosthesis or disease, are currently significantly less frequent, the presence of ischemic heart and arterial disease, that prompted treatment in about one-fourth of patients in the original 1996 study, has now almost entirely disappeared. The high prevalence of patients treated with VKAs for arterial diseases may well be the explanation for the very high rate of thrombotic complications recorded in the ISCOAT 1996/7 and not observed in the current cohort. There is now general awareness of the fact that VKAs therapy is not the best indication, and is less effective for treatment of arterial diseases. The quality of anticoagulation control is similar in both studies, with similar TTR values. However, in spite of the sharp increase in the number of very elderly patients, a population generally expected to carry greater risk of bleeding during VKA (especially intracranial), the rates of major bleedings are almost identical (an annual 1.38% now versus 1.39% 20 years ago), with similar incidence of intracranial or gastrointestinal events, and a trend for fewer fatal events. A significant difference is detected in the incidence of thrombotic complications that was as high as 3.5% annually in the 1997 report but fell drastically to 0.53% in the present report. The reduction is particularly evident in VTE patients, in whom thrombotic events fell from 4.8 to 0.8% annually (
p = 0.01), and for events occurring during the first 3 months of treatment (
p = 0.01) (Table
4). It is reasonable to surmise that the Italian anticoagulation clinics have markedly improved the way they manage patients, in particular those with recent VTE, by avoiding as far as possible periods of under-anticoagulation and improving the bridging with a parenteral anticoagulant especially during the first months of treatment. This improved management can in part be attributed to the education the Federation provides participant centers [
31,
32]. An increased ability to perform more gradual and accurate induction phases of anticoagulation is a likely explanation for the much better results in the initial 3 months of VKA, a period that has been shown to be crucial for VKA-treated patients [
33]. More patients died during treatment in the present (6.1%) versus previous report (3.7%) for causes apparently not correlated with the VKA treatment. This result is not surprising if we take into account the much higher prevalence of very elderly patients included in the present study.
In conclusion, the current ISCOAT 2016 study analyzing a large, inception-cohort of patients treated with VKA for different indications monitored in Italian anticoagulation clinics, reports very good clinical results, with rates of major bleeding and thrombotic complications lower than those reported in randomized trials and even in observational registries. When the current results are compared with those of the 1996 ISCOAT study, which had the same design and also involved anticoagulation clinics of the Italian FCSA Federation [
1,
2], important differences are found: the age of treated patients is markedly increased in association with a drastic increase in patients treated for AF, while very few patients are treated for ischemic heart disease or other arterial diseases. Notwithstanding the older age of patients included in the current study, the rate of major bleedings and in particular of intracranial hemorrhages is similar in both studies. In contrast, a marked reduction in thrombotic complications is recorded, especially involving patients treated for VTE and during the first 3 months of treatment, pointing to a substantial improvement in the management of the initial phase of anticoagulation at our anticoagulation clinics, especially in VTE patients.
The following Investigators and Centers, affiliated to the Italian Federation of Anticoagulation Clinics (FCSA), participated to the FCSA-START-Registry and contributed to the present study
Sophie Testa, Oriana Paoletti, UO Laboratorio Analisi, Centro Emostasi e Trombosi A O Istituti Ospitalieri di Cremona, Cremona; Giuliana Guazzaloca, UO di Angiologia e Malattie Coagulazione, AOU S. Orsola-Malpighi, Bologna, Bologna; Daniela Poli, Rossella Marcucci, SOD Malattie Aterotrombotiche, Azienda Ospedaliero Universitaria-Careggi, Firenze; Vittorio Pengo, Dipartimento di Scienze Cardio-Toraco-Vascolari, Centro Trombosi, AOU Padova, Padova; Anna Falanga, Teresa Lerede, USC SIMT, Centro Emostasi e Trombosi, Ospedale Papa Giovanni XXIII, Bergamo; Antonietta Piana, Francesco Cibecchini, Centro Prevenzione e Cura Malattie Tromboemboliche Azienda Ospedaliera Universitaria San Martino-IST, Genova; Lucia Ruocco, U.O. Analisi chimico-cliniche, Azienda Ospedaliero Universitaria Pisana, Pisa; Giuliana Martini, Centro Emostasi Spedali Civili Di Brescia, Brescia; Simona Pedrini, Federica Bertola, Servizio di Laboratorio, Istituto Ospedaliero Fondazione Poliambulanza Brescia; Lucilla Masciocco, Pasquale Saracino, Angelo Benvenuto, UOC Medicina Interna, Centro Controllo Coagulazione, Presidio Ospedaliero Lastaria, Lucera (Foggia); Claudio Vasselli, Laboratorio Patologia Clinica, Policlinico Casilino, Roma; Eugenio Bucherini, SS Medicina Vascolare-Angiologia, Ambulatorio Anticoagulanti, Ospedale Civile di Faenza, Faenza (Ravenna); Andrea Toma, Pietro Barbera, UOC di Patologia Clinica, Ambulatorio Terapia Anticoagulante Orale, O.C. “L.Cazzavillan” Arzignano, (Vicenza); Antonio Insana, SC Patologia Clinica, Ospedale Santa Croce Moncalieri, Moncalieri (Torino); Carmelo Paparo, Patologia Clinica, Ospedale Maggiore Chieri (Torino); Serena Rupoli, AOU- Ospedali Riuniti Ancona, Ancona; Giuseppe Malcangi, Centro Emofilia e Trombosi, Policlinico di Bari, Bari; Rossella Sangiorgio, Centro TAO Struttura Semplice Emostasi e Trombosi Lecco; Maddalena Loredana Zighetti, SIM TAO San Paolo, Milano; Catello Mangione, Sezione Trasfusionale Ospedale di Galatina, Galatina (Lecce); Enrica Agostinelli Servizio Trasfusionale e di Ematologia, Treviglio Bergamo; Walter Ageno, Giovanna Colombo, UO. Medicina I, Ospedale di Circolo, Varese; Vincenzo Oriana, Centro Emofilia - Presidio Morelli- Reggio Calabria; Nicola Lucio Liberato, Azienda Ospedaliera Provincia di Pavia, UO Medicina Interna Ospedale di Casorate Primo, Pavia; Paola Casasco, Servizio Medicina Trasfusionale Tortona (Alessandria); Alberto Tosetto, Divisione di Ematologia, Ospedale San Bortolo, Vicenza;