Beneficial Effects of a Perindopril/Indapamide Single-Pill Combination in Hypertensive Patients with Diabetes and/or Obesity or Metabolic Syndrome: A Post Hoc Pooled Analysis of Four Observational Studies.

INTRODUCTION: To assess real-life effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in patients with hypertension (HT) and type 2 diabetes mellitus (T2DM), obesity and/or metabolic syndrome (MetS). METHODS: This post hoc analysis pooled raw data from four large observational studies (FORTISSIMO, FORSAGE, ACES, PICASSO). Patients, most with uncontrolled blood pressure (BP) on previous treatments were switched to Per/Ind (10 mg/2.5 mg) SPC at study entry. Office systolic and diastolic blood pressures (SBP and DBP) were measured at baseline, 1 month and 3 months. RESULTS: In the overall pooled population (N = 16,763), mean age was 61 ± 12 years, HT duration 11 ± 8 years, and baseline SBP/DBP 162/94 mmHg. T2DM, obesity and MetS were present in 21%, 49% and 27% of patients, respectively. Subgroups had similar mean age and HT duration to the overall population; patients with T2DM were slightly older (64 ± 10 years) with a longer HT duration (13 ± 8 years). Mean BP was approximately 160/95 mmHg in each subgroup. At 1 month, mean SBP decreased by approximately 20 mmHg in the overall population, and by a further 10 mmHg at 3 months. Similar results were observed in the three subgroups, with mean changes from baseline at 3 months of - 28 ± 15/- 13 ± 10 in T2DM; - 30 ± 15/- 14 ± 10 in obesity; and - 31 ± 15/- 15 ± 9 mmHg in MetS. BP decreases were greatest in patients with grade II or grade III HT. BP control rates (< 140/90 mmHg or 140/85 mmHg for T2DM) at 3 months were 59% in T2DM, 67% in obese, and 66% in MetS. No specific safety concerns were raised, particularly concerning ionic (Na, K) or metabolic profiles. CONCLUSIONS: Switching to Per/Ind SPC led to rapid and effective BP decreases in patients with T2DM, obesity, or MetS. BP control was achieved in 6-7 out of 10 previously treated but uncontrolled patients. Treatment was well tolerated. The results confirm the beneficial effects of a Per/Ind SPC for difficult-to-control patient populations.

Trimetazidine and Bisoprolol to Treat Angina in Symptomatic Patients: Post Hoc Analysis From the CHOICE-2 Study.

INTRODUCTION: Angina is the cardinal symptom of chronic coronary syndrome (CCS), which is the leading cause of death worldwide. As such, the control of angina is important. The current guidelines recommend beta blockers (BB) or calcium channel blockers to reduce angina, yet many patients with stable angina remain symptomatic. It has been suggested that combining trimetazidine (TMZ), an anti-ischemic agent, with a BB is beneficial for symptomatic patients. Bisoprolol, a BB, is often used to treat patients with CCS, yet no data are currently available regarding the efficacy of bisoprolol combined with TMZ in patients who remain symptomatic despite receiving bisoprolol. METHODS: The aim of this post-hoc analysis of the CHOICE-2 study was to evaluate the efficacy and safety of TMZ 35 mg twice daily in combination with different bisoprolol doses in symptomatic patients with stable angina patients receiving hemodynamic therapy in a real-world clinical setting. RESULTS: This analysis involved 221 patients (mean [± standard deviation] age 64.8 ± 8.9 years) with stable angina. The mean number of weekly angina episodes gradually fell from 6.2 ± 5.3 at inclusion (M0) to 1.5 ± 1.9 at 6 months after treatment initiation (M6) with combined TMZ-bisoprolol therapy (P < 0.001). The number of patients assessed to be angina-free increased almost sixfold from 5.4% (12/221) at M0 to 33.9% (74/221) at M6. Exercise capacity improved, as measured by walking distance, from 308 ± 207 m at M0 to 497 ± 253 m at M6 (P < 0.05). The number of patients with Canadian Cardiovascular Society class 1 angina increased by tenfold during the study, whereas those with class 3 angina decreased by threefold. CONCLUSION: The TMZ-bisoprolol combination is a rapidly effective treatment for reducing the frequency of angina attacks and the use of short-acting nitrates in patients with stable angina in a real-world clinical setting. The benefits of this combination therapy was observed as early as 2 weeks after treatment initiation and the treatment was well tolerated. TRIAL REGISTRATION: ISRCTN identifier: ISRCTN65209863.

Effectiveness of Perindopril/Indapamide Single-Pill Combination in Uncontrolled Patients with Hypertension: A Pooled Analysis of the FORTISSIMO, FORSAGE, ACES and PICASSO Observational Studies.

INTRODUCTION: Our objective was to determine the effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in a broad range of patient profiles, including subgroups with varying hypertension severity, age and cardiovascular risk profiles. METHODS: Patient data from four large prospective observational studies (FORTISSIMO, FORSAGE, PICASSO, ACES) were pooled. In each study, patients already treated for hypertension were switched to Per/Ind 10/2.5 mg SPC and systolic and diastolic blood pressure (SBP/DBP) measured at the 1-month (M1) and 3-month (M3) visits. Study endpoints included change in SBP and DBP from baseline to M1 and M3 and the percentage of patients achieving BP control (SBP/DBP < 140/90 mmHg for patients without diabetes or < 140/85 mmHg for patients with diabetes). RESULTS: A total of 16,763 patients were enrolled and received Per/Ind (94% received the full dose of 10/2.5). Mean patient age was 61.4 years (36% were ≥ 65 years old), 57% were women, and 16% had isolated systolic hypertension (ISH). Mean baseline office SBP/DBP was 162/94 mmHg, and mean duration of hypertension was 11 years. Cardiovascular risk factors and comorbid conditions were common in this population. Significant mean reductions in SBP (- 23 mmHg) and DBP (- 11 mmHg) were observed at M1 compared with baseline (P < 0.001), which were maintained at M3 (- 30 mmHg and - 14 mmHg, respectively). At M3, BP control was achieved by 70% of patients (78% for ISH). In patients with SBP ≥ 180 mmHg at baseline (grade III hypertension), the mean SBP/DBP decrease was - 51/- 20 mmHg and 53% achieved BP control. Per/Ind was well tolerated with an overall rate of adverse events of 1.3%, most frequently cough and dizziness at rates of 0.3% and 0.2%, respectively. CONCLUSION: In this hypertensive population including difficult-to-control patient subgroups, switching to Per/Ind 10/2.5 mg SPC led to rapid and important reductions in BP. BP control was achieved in 70% of patients overall in an everyday practice context.

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

INTRODUCTION: Trimetazidine (TMZ) is an antianginal agent that acts directly at the myocardial cell level and which is now available in a once-daily (od) formulation. METHODS: ODA, a 3-month, observational, multicenter study in Russia, assessed the effectiveness and tolerability of TMZ 80 mg od in patients with stable angina and persisting symptoms, in real-life settings. The present analysis explored the effects of adding TMZ to background antianginal treatment with respect to the duration of stable angina. RESULTS: A total of 3032 patients were divided into four groups according to stable angina pectoris duration since diagnosis, ranging from less than 1 year to more than 10 years. A decrease in frequency of angina attacks was observed, including in patients with angina duration < 1 year, in whom the frequency of weekly angina attacks decreased from 3.8 ± 2.9 to 1.4 ± 1.7 at 1 month and 0.6 ± 1.0 at 3 months. Short-acting nitrate consumption and proportion of angina-free patients decreased, and self-reported physical activity and adherence to antianginal therapy improved in all patient groups, including recently diagnosed patients and starting already at month 1. CONCLUSIONS: Addition of TMZ 80 mg od to antianginal treatment was effective in reducing the frequency of angina attacks and the use of short-acting nitrates, improving Canadian Cardiovascular Society (CCS) class, self-reported physical activity, and adherence to antianginal therapy. These beneficial effects were observed in patient groups with different durations of stable angina, suggesting an opportunity for decreasing angina burden even in recently diagnosed patients. TRIAL REGISTRATION: ISRCTN registry Identifier, ISRCTN97780949.

Effectiveness of Long-acting Trimetazidine in Different Clinical Situations in Patients with Stable Angina Pectoris: Findings from ODA Trial.

INTRODUCTION: Trimetazidine (TMZ) has been shown to be efficacious for angina treatment. The TMZ 80-mg formulation allows one-daily (od) dosage, which could improve symptom control and adherence. METHODS: The 3-month, observational, multicenter, prospective ODA (antianginal effectiveness and tolerability of trimetazidine modified release 80 mg Once Daily in stable Angina patients in real-world practice) study assessed TMZ 80 mg od effectiveness in stable angina patients with persistent symptoms despite therapy. Two clinical situations were compared: patients who initiated treatment with TMZ 80 mg od (initiation group) and patients who were previously treated with TMZ 20 mg thrice daily (tid) or TMZ 35 mg MR twice daily (bid) and switched to TMZ 80 mg od (switch group). Number of angina attacks, short-acting nitrate (SAN) consumption, self-reported patient daily activity, Canadian Cardiovascular Society (CCS) class, adherence to antianginal therapy, overall efficacy and tolerability were assessed. RESULTS: A significant decrease in weekly number of angina attacks was observed for both the initiation group (n = 1841 patients) from 4.8 ± 3.5 at baseline to 0.9 ± 1.4 at 3 months (M3) (P < 0.001), and the switch group (n = 1216 patients) from 4.4 ± 1.3 at baseline to 0.9 ± 1.3 at M3 (P < 0.001). Significant reduction in SAN consumption and improvement in CCS class were observed for both groups. Adherence to antianginal therapy improved in both groups at 1 month (M1) and M3. Overall effectiveness of TMZ 80 mg od was rated by physicians as "very good" (68% initiation group, 70% switch group), "good" (31% initiation group, 29% switch group), "moderate" (1%, both groups) or "poor" (< 1%, both groups). Overall tolerability of TMZ 80 mg od was rated by physicians as "very good" (75%), "good" (25%) or "moderate" (< 1%) in both groups. CONCLUSIONS: TMZ 80 mg od, in association with other antianginal therapy, effectively reduced angina attacks and SAN consumption and improved physical activity and adherence to antianginal therapy both in patients initiating TMZ treatment and those switching from a bid or tid formulation. TRIAL REGISTRATION: ISRCTN registry Identifier, ISRCTN97780949. FUNDING: Servier. Plain language summary available for this article.

Anti-Anginal Effectiveness and Tolerability of Trimetazidine Modified Release 80 Mg Once Daily in Stable Angina Patients in Real-World Practice.

INTRODUCTION: Trimetazidine (TMZ) was shown to reduce angina symptoms and increase the exercise capacity in stable angina (SA) patients. A new formulation allowing a once-daily (od) dosage could improve patients' satisfaction and adherence. METHODS: ODA was a 3-month, observational, multicenter, prospective Russian study in SA patients with persistent symptoms despite therapy. Angina attack frequency, short-acting nitrate (SAN) consumption, adherence to antianginal medications, and overall efficacy and tolerability of TMZ 80 mg od were assessed in a real-world setting. RESULTS: A total of 3066 patients were included (mean age 62.8, 48% male). After 3 months, TMZ 80 mg od treatment led to a significant (p < 0.001) decrease in angina attack frequency (from 4.7 ± 3.5 to 0.9 ± 1.3/week) and SAN use (from 4.5 ± 3.9 to 0.7 ± 1.3/week). Overall tolerability and effectiveness were rated as "very good" by the majority of physicians. Medication adherence improved significantly, with good adherence reported by 56% of patients (vs. 24% at baseline, p < 0.0001) and non-adherence by 3% (vs. 36% at baseline, p < 0.0001) at month 3. Patient satisfaction with TMZ od was 9.5 [on a scale of 1 to 10 (very satisfied)]. Patients reported improved physical activity: more patients reported no limitations (15% vs. 1% at baseline p < 0.01), slight limitation (46% vs. 5% at baseline, p < 0.001) or moderate limitation (30% vs. 23%, p < 0.01) and fewer patients reported substantial limitation (8% vs. 52% at baseline, p < 0.001) or very marked reduction (1% vs. 19% at baseline, p < 0.01) at month 3. CONCLUSION: In this prospective, observational study, TMZ 80 mg od effectively reduced angina attacks and SAN consumption, improved physical activity and adherence and was well tolerated in chronic SA patients. TRIAL REGISTRATION: ISRCTN registry Identifier, ISRCTN97780949. FUNDING: Servier. Plain language summary available for this article.

The Effectiveness of Trimetazidine Treatment in Patients with Stable Angina Pectoris of Various Durations: Results from the CHOICE-2 Study.

INTRODUCTION: Trimetazidine (TMZ) has been shown to reduce angina symptoms and to increase exercise capacity in randomized clinical trials, but more extensive data would be useful to assess its effects in real-world clinical practice and in patients with different durations of disease. METHODS: CHOICE-2 was a Russian, multicenter, 6-month, open-label, prospective observational study that assessed the effect of adding TMZ modified release 35 mg bid to antianginal treatment in a real-world setting. The present analysis of CHOICE-2 results explored the effects of adding TMZ to background antianginal therapies with regard to the duration of stable angina. RESULTS: A total of 741 patients with known durations of disease were divided into four groups according to stable angina pectoris (AP) duration, ranging from less than 1 year to more than 9 years. Addition of TMZ led to a significant decrease in the frequency of angina attacks and in the use of short-acting nitrates in all groups. In patients with recently diagnosed angina (AP duration < 1 year), the average number of angina attacks per week decreased significantly from 3.75 ± 4.63 to 0.67 ± 1.51 and in those with advanced disease (AP duration > 9 years) from 5.63 ± 5.24 to 1.32 ± 2.07. Angina-free walking distance also improved significantly. Addition of TMZ also improved patient well-being. Results were achieved rapidly (within 2 weeks), were maintained over 6 months, and were obtained in all patient groups regardless of angina duration. CONCLUSION: TMZ added to other antianginal therapies proved to be effective for reducing angina attacks and short-acting nitrate use, increasing angina-free walking distance, and improving patient well-being in a real-life setting, irrespective of angina duration, including patients with recently diagnosed angina. This provides an opportunity for intensification of treatment early on in the disease process, with the aim of decreasing angina burden and improving patient quality of life. FUNDING: Servier. TRIAL REGISTRATION: ISRCTN identifier ISRCTN65209863. Plain language summary available for this article.

Optimization of heart rate lowering therapy in hospitalized patients with heart failure: Insights from the Optimize Heart Failure Care Program.

BACKGROUND: Hospitalization is an opportunity to optimize heart failure (HF) therapy. As optimal treatment for hospitalized HF patients in sinus rhythm with heart rate≥70bpm is unclear, we investigated the impact of combined beta-blocker (BB) and ivabradine versus BBs alone on short and longer term mortality and rehospitalization. METHODS AND RESULTS: A retrospective analysis was performed on 370 hospitalized HF patients with heart rate≥70bpm (150 BB+ivabradine, 220 BB alone) in the Optimize Heart Failure Care Program in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Russia, Ukraine, and Uzbekistan, from October 2015 to April 2016. RESULTS: At 1month, 3months, 6months and 12months, there were fewer deaths, HF hospitalizations and overall hospitalizations in patients on BB+ivabradine vs BBs alone. At 12months, all-cause mortality or HF hospitalization was significantly lower with BB+ivabradine than BBs (adjusted hazard ratio [HR] 0.45 (95% confidence interval [CI] 0.32-0.64, P<0.0001). Significantly greater improvement was seen in quality of life (QOL) from admission to 12months with BB+ivabradine vs BBs alone (P=0.0001). With BB+ivabradine, significantly more patients achieved ≥50% target doses of BBs at 12months than on admission (82.0% vs 66.6%, P=0.0001), but the effect was non-significant with BBs alone. CONCLUSIONS: Heart rate lowering therapy with BB+ivabradine started in hospitalized HF patients (heart rate≥70bpm) is associated with reduced overall mortality and re-hospitalization over the subsequent 12months. A prospective randomized trial is needed to confirm the advantages of this strategy.

Efficacy of Ivabradine in Combination with Beta-Blockers Versus Uptitration of Beta-Blockers in Patients with Stable Angina (CONTROL-2 Study).

INTRODUCTION: Heart rate (HR) reduction is an integral part of antianginal therapy, but many patients do not reach the guideline-recommended target of less than 60 bpm despite high use of beta-blockers (BB). Failure to uptitrate BB doses may be partly to blame. To explore other options for lowering HR and improving angina control, CONTROL-2 was initiated to compare the efficacy and tolerability of the combination of BBs with ivabradine versus uptitration of BBs to maximal tolerated dose, in patients with stable angina. METHODS: This multicenter, open, randomized study included 1104 patients with Canadian Cardiovascular Society (CCS) class II or III stable angina, in sinus rhythm, and on background stable treatment with non-maximal recommended doses of BBs. Consecutive patients were allocated to ivabradine + BB or BB uptitration in a 4:1 ratio. RESULTS: At the end of the study (week 16), addition of ivabradine to BB treatment and BB uptitration resulted in reduction in HR (61 ± 6 vs. 63 ± 8 bpm; p = 0.001). At week 16, significantly more patients on ivabradine + BB were in CCS class I than with BB uptitration (37.1% vs. 28%; p = 0.017) and significantly more patients were angina-free (50.6% vs. 34.2%; p < 0.001). Patient health status based on the visual analogue scale (VAS) was also better in the ivabradine + BB group. Adverse events (AEs) were significantly more common with BB uptitration than with the ivabradine + BB combination (18.4% vs. 9.4%, p < 0.001). CONCLUSION: In patients with stable angina, combination therapy with ivabradine + BB demonstrated good tolerability, safety, and more pronounced clinical improvement, compared to BB uptitration. TRIAL REGISTRATION: ISRCTN30654443. FUNDING: Servier.

Real-world Evidence for the Antianginal Efficacy of Trimetazidine from the Russian Observational CHOICE-2 Study.

INTRODUCTION: The guidelines recommend a beta-blocker or calcium channel blocker as the first-line medication for angina, supplemented by other agents for additional symptoms. One such agent is trimetazidine (TMZ), which has been shown to reduce the frequency of anginal episodes and improve exercise performance without affecting haemodynamic parameters. However, extensive real-world evidence for its efficacy in combination with first-line therapies has been lacking. METHODS: The aim of this large-scale, Russian, multicentre, 6-month, open-label, prospective observational study was to assess the effect of adding TMZ modified release 35 mg bid to background antianginal therapy in the real-world clinical setting. RESULTS: The study included 896 patients: 54% women, aged 29-90 years (42.6% >65 years), 63% with class II angina, and receiving beta-blockers alone or in combination (93%). Add-on TMZ reduced angina frequency and short-acting nitrate use within 2 weeks (both p < 0.0001) regardless of background therapy and maintained this effect over 6 months. It increased the proportion of patients with class I angina sixfold while decreasing that of class 3 angina almost fourfold. It also improved walking distance and well-being at 6 months (both p < 0.0001). Treatment was well tolerated. CONCLUSION: Add-on TMZ is a safe and rapidly effective treatment for reducing angina attacks and nitrate use in the real-world clinical setting. It also increases exercise capacity and well-being. These effects are observed within 2 weeks and persist for at least 6 months.