Effectiveness of Trimetazidine in Patients with Stable Angina Pectoris of Various Durations: Results from ODA

Ischemic heart disease remains today a major cause of mortality for both sexes [1, 2] and the incidence of stable angina pectoris (AP) has been reported to increase with age in both sexes [3]. Angina prevails over myocardial infarction and heart failure as a reason for years lived with disability due to ischemic heart disease [4]. Ischemia, angina, and physical limitation are strongly predictive of major adverse cardiovascular events and poor survival [5‐8], even after percutaneous coronary intervention (PCI) [9]. Thus, alleviating angina symptoms and improving patients’ quality of life remains an important goal in the treatment of angina patients [10, 11]. Noteworthy, the latest ESC CCS Guidelines 2019, for the first time ever, gave a specific temporal definition of the term “recently diagnosed” CCS patients, which is patients within 1 year of the diagnosis, focusing on the importance of a tight follow-up and timely angina alleviation in this specific group of angina patients. Also in the same document, there is a specific part dedicated to the patients with a long-standing diagnosis of chronic coronary syndrome where the authors highlight the importance of “life-long treatment and surveillance” [11]. Yet, importantly, more than 30% of patients continue to experience symptoms despite antianginal treatment [12] and the rate of angina remains high even after successful revascularization in the course of the disease and is among the most common factors affecting rehospitalization [13‐15]. Moreover, angina patients live longer nowadays and often have comorbidities [16], which increases the number of medications thus impacting adherence. This could be even more pronounced in patients who have had angina for a long time.

Patients with angina can remain symptomatic despite standard hemodynamic treatment [17]. Combining hemodynamic drugs does not necessarily translate into improved antianginal efficacy [18, 19], as in spite of hemodynamic treatment combinations, patients remain symptomatic [20]. Trimetazidine (TMZ) acts directly at the myocardial cell level [21] and its addition to the antianginal therapy offers an opportunity for treatment optimization.

The ODA (anti-anginal effectiveness and tolerability of trimetazidine modified release 80 mg once daily in stable angina patients in real-world practice) study assessed the effectiveness and tolerability of TMZ 80 mg once daily (od) in stable angina patients in a real-life clinical practice setting in Russia and its rationale, design, and main results have been previously published [22]. In the present analysis of the ODA study, we sought to assess the effect of TMZ 80 od addition to hemodynamic therapy with regard to angina duration focusing on its impact on effectiveness and adherence to treatment in the patients corresponding to the new ESC CCS Guidelines definition of “recently diagnosed” CCS patients, as well as on patients with a diagnosis duration longer than 1 year, corresponding to the group of patients with long-standing diagnosis of CCS.

ODA was a 3-month observational, multicenter, prospective study in 3066 stable angina patients with persistent symptoms despite therapy, conducted in Russia from March 2017 to June 2017 in a real-world clinical setting. The methods and main findings of this study have been published previously [22]. Patients were treated according to current recommendations for coronary artery disease management and their inclusion was exclusively determined by the decision of the physician regarding medical meaningfulness and indication for treatment with TMZ od 80 mg.

Data were collected at baseline, month 1, and month 3, regarding the number of angina attacks, short-acting nitrate (SAN) consumption in the week prior to the visit, Canadian Cardiovascular Society (CCS), patient self-assessment of physical activity, and adherence to antianginal treatment. For self-assessment of their daily activity, patients rated the impact of angina on their daily activity on a scale of 1–10 and answers were categorized into the following categories: no limitation (0), slight limitation (1–2), moderate limitation (3–4), substantial limitation (5–7), and very marked reduction (8–10). Adherence to treatment was assessed using a six-item questionnaire [23], with the following definitions: good adherence—patient responded “NO” to all questions; moderate adherence—patient responded “YES” to 1–2 questions; non-adherence—patient responded “YES” to three or more questions.

A total of 3032 patients were divided into four groups according to AP duration since diagnosis: (1) group 1, AP duration less than 1 year (n = 88); (2) group 2, AP duration 1–5 years (n = 1323); (3) group 3, AP duration 5–10 years (n = 854); and (4) group 4, AP duration more than 10 years (n = 767). Demographic and baseline characteristics are presented in Table 1. As AP duration increased, patients were on average older, the proportion of patients aged ≥ 65 years increased and the proportion of patients with some comorbidities (arterial hypertension, diabetes) and with history of myocardial infarction also increased. Unfavorable family history of coronary artery disease (CAD) did not seem to be related to AP duration.

Antianginal treatments at baseline are shown in Table 2. Monotherapy was frequent in all patient groups, even those with long disease duration. The proportion of patients on monotherapy with any hemodynamic antianginal drug was 54.7% in group 1, 43.4% in group 2, 37.6% in group 3, and 30.4% in group 4. Beta-blockers (BB) were the most often prescribed drug, either alone or in combination. In patients with longer duration of AP, the frequency of monotherapy with BB was significantly lower compared with that in patients with short (< 1 year) AP duration. The proportion of patients on monotherapy with CCB or long-acting nitrates was low overall and did not differ between groups with different AP duration. A combination of BB + CCB was received by one in three or four patients, with no significant differences observed between patient groups. The proportion of patients treated with a combination of BB + ivabradine or CCB + long-acting nitrates was low and, in most cases, did not differ between groups with different duration of the disease. The frequency of administration of the triple combination of BB + CCB + long-acting nitrates increased with increasing disease duration and was significantly higher in groups 3 and 4.

At baseline, the distribution of patients according to CCS class did not differ between patients with a disease duration of less than 1 year and those with AP duration of 1–5 years (Table 3). With longer AP duration (groups 3 and 4), a significant increase in the proportion of patients with CCS class III and decrease in the proportion of patients with CCS Class I were observed. When TMZ 80 mg od was added to treatment, in patients with angina duration < 1 year, the proportion of patients with CCS Class I increased by twofold by month 1 (56.8%) and by almost threefold by month 3 (80.7%). Similar improvements were observed in patients with 1–5 years angina duration and were even more pronounced in patients with more than 5 years of angina duration. Significant decreases in proportion of patients with CCS Class III compared to baseline were observed in all patient groups.

At baseline, the number of angina attacks per week was greater in patients with longer angina duration. Significant decreases in the frequency of angina attacks were observed already at month 1 across all patient groups, with a further decrease observed at month 3 (Fig. 1). In patients with angina duration < 1 year, the frequency of weekly angina attacks decreased by almost threefold, reaching a mean of 1.4 ± 1.7 and by sixfold at month 3, reaching a mean of 0.6 ± 1.0. Similarly, a significant decrease in short-acting nitrate (SAN) consumption was observed starting from month 1 in all patient groups (Fig. 2). The decrease in the frequency of angina attacks in patients with a disease duration of more than 10 years was significantly more pronounced, but the frequency of angina attacks at 3 months remained higher in this patient group than in patients with shorter disease duration. Similar changes were observed with regard to SAN consumption.

The proportion of angina-free patients increased significantly and consistently in all groups, starting already at month 1, with the highest proportion of angina-free patients observed in the group of recently diagnosed patients (70% of patients at month 3) (Fig. 3).

At baseline, physical activity as self-assessed by patients was less limited in patients with AP duration of less than 1 year (Fig. 4). Patients with a disease duration of more than 1 year were more likely to have moderate limitation, substantial limitation, or very marked reduction of physical activity. In patients treated with TMZ 80 mg OD, an improvement in physical activity was observed already at 1 month of therapy, in all patient groups, with further improvement at month 3. The proportion of patients with no or slight limitation of physical activity increased and the proportion of patients with substantial limitation or very marked reduction significantly decreased already after 1 month of therapy.

At baseline, adherence to antianginal therapy was lower as disease duration increased. Good adherence to antianginal therapy increased significantly in all patient groups at month 1 and continued to increase by month 3 (Fig. 5). The highest proportion of patients with good adherence at month 3 (over 70%) was observed in patients with disease duration of less than 1 year.

In the present analysis, we assessed the effect of introducing TMZ 80 mg od to the therapy of stable angina patients with various durations of disease, who were symptomatic despite antianginal therapy, in real clinical practice conditions.

Improvements in CCS Class were observed across all patient groups, with a significant increase in the proportion of CCS Class I patients. Weekly angina attacks and SAN consumption were significantly reduced in all patient groups, regardless of disease duration. The results were significant already at month 1 and continued to improve until month 3. At baseline, there were no angina-free patients in any of the groups. An increase in the proportion of angina-free patients was observed in all groups, particularly in recently diagnosed patients (< 1 year), with half of the patients being asymptomatic at visit 1 and 70% at month 3. Including TMZ in the therapeutic scheme also improved self-reported physical capacity and adherence to antianginal therapy, which might be related to the improvement observed in treatment effectiveness, in all patient groups.

In the newly diagnosed patient group, we observed the highest proportion of patients with CCS Class I, which reached 57% at month 1 in group 1 and 81% at month 3, and the lowest frequency of angina attacks and SAN consumption, although it must be kept in mind that this patient group was in a better state with regard to these parameters at baseline, compared to the other patient groups. Patients with short angina duration (< 1 year) were the most adherent at baseline, which could be related to the fact that they were younger and had fewer comorbidities, and thus were probably taking fewer pills. However, there was still room for adherence to improve, reaching 70% of patients with good adherence at month 3.

Introduction of TMZ led to pronounced improvements in patients with long duration of disease (> 10 years), but the significant improvements observed in patients diagnosed within 1 year highlights the opportunity to improve the clinical status with trimetazidine 80 mg od early on after the diagnosis. This group corresponds to the definition of the new Chronic Coronary Syndrome (CCS) 2019 guidelines of “recently diagnosed patients” (< 1 year from diagnosis) [11].

According to these guidelines, fast symptom relief with timely check-up of the medical treatment result within 2–4 weeks is recommended. Angina is a multifactorial syndrome [11, 24] and symptom alleviation with more than one antianginal drug is described in the guidelines [11]. Very often, the combination of hemodynamic drugs is insufficient to control angina symptoms [18, 20]. There is no evidence from randomized controlled trials of the superiority of the so-called “first-line” antianginal agents coming from a direct comparison with antianginal therapies [25].

The new CCS Guidelines rather recommend a new treatment paradigm of antianginal medical treatment, which should be tailored around the patient profile, co-morbidities, drug tolerance, and potential drug interactions, which is why the guidelines also recommend achieving symptom alleviation with early combination of “first-line” and “second-line” antianginal drugs.

In such a patient-tailored approach, “second-line” drugs like TMZ can be used early alongside “first-line” drugs (beta-blockers, CCBs), for more efficient antianginal relief. TMZ in combination with beta-blockers has been shown to be superior to beta-blockers alone, and to combination of beta-blockers with long-acting nitrates [26, 27]. Therefore, introducing TMZ in combination with a beta-blocker in patients who are still symptomatic despite treatment with the beta-blocker provides an opportunity for more efficient and earlier symptom alleviation. In our study, despite being symptomatic, many patients were on monotherapy at baseline. Even in patients with more than 5 years of angina duration, the proportion of patients treated only with a beta-blocker was 24–30%. Introducing TMZ was particularly beneficial for patients with < 1-year angina duration (recently diagnosed), where more than 50% were taking only a beta-blocker in their therapeutic antianginal scheme. Undertreatment of symptomatic angina patients in clinical practice is not a rare phenomenon [12, 17, 28, 29]. It has been reported that angina is under-treated in clinical practice with 38.5% of patients with daily or weekly angina taking only one antianginal drug [12]; in a large study including more than 12,000 post primary revascularization MI patients, 68% of the patients who reported angina within 6 weeks after the procedure remained treated only with a with beta-blocker [29]. As many patients at diagnosis are already treated with a hemodynamic antianginal drug for reasons other than angina (beta-blockers 50.3%, CCB 17%, LAN 5%) [30], early inclusion of TMZ 80 mg od might be beneficial for these patients, instead of up titrating or adding another hemodynamic agent, which might be related to compromising tolerability due to the enhanced hemodynamic effects of the hemodynamic agent, which might compromise adherence [31] or might have doubtful additional anti-angina efficacy [18].

According to the new guidelines, in the context of antianginal drugs, optimal medical therapy can be defined as the treatment that satisfactorily controls symptoms with effective symptom alleviation, maximum adherence, and minimum side effects [11]. TMZ od is therefore an important part of antianginal therapy, as it effectively improves angina symptoms and shows a good tolerability profile. Tolerability was not assessed in this analysis, but as reported in the main analysis, there were only 0.3% suspected adverse drug reactions [22].

Including TMZ 80 mg od to antianginal therapy effectively improved CCS class, frequency of angina attacks and SAN consumption, self-reported patient activity and adherence to antianginal treatment in all patient groups irrespective of angina duration, including patients with recently diagnosed angina, in real clinical practice conditions, thus providing an opportunity to improve symptoms and quality of life whatever the duration of the disease, but most importantly, to provide effective angina relief from the very beginning of diagnosis and treatment.