References:

  1. Ranexa®. Summary of Product Characteristics, Last EMA update October 2020.
  2. Wilson, S.R. et al., J Am Coll Cardiol 2009;53(17):1510-6.
  3. Stone P.H. et al., J Am Coll Cardiol 2006;48(3):567-75.
  4. Diedrichs H. et al., J Clin Exp Cardiology 2015;6:12.
  5. López-Sendón J. et al., Eur J Prev Cardiol. 2012;19:952-9.
  6. Virani, 2023, 2023 AHA/ACC/ASPC/NLA/PCNA Guideline for Chronic Coronary Disease, Circulation, 148(13), E148-E148.
  7. Vrints, C. et al., 2024 ESC Guidelines for Chronic Coronary Syndromes, European Heart Journal, p.eheal77.

References:

  1. Arnold SV et al. Circ Cardiovasc Qual Outcomes. 2016. September;9(5): 554–559 doi:10.1161/CIRCOUTCOMES. 116.002781
  2. Kureshi F et al. Clin Cardiol. 2017 January ; 40(1): 6–10.

defined as the physician reporting a lower frequency category of angina than the patient

Frequency Distribution of Patient-Reported Angina Episodes in the Past Month1

Among the 33% of patients who reported angina in the previous month:

Patient reported angina frequency in 411 Patients with CAD and angina symptoms over the prior month who completed the Seattle Angina Questionnaire (SAQ) prior to their clinic visit1

The Angina Prevalence and Provider Evaluation of Angina Relief (APPEAR) was a cross-sectional, multicenter study designed to assess the frequency of angina and its impact on quality of life among 1257 outpatients with coronary artery disease across 25 US sites. Eligible patients had documented history of CAD and -1 prior office visit at the practice site. Angina was assessed directly from patients using the Seattle Angina Questionnaire Angina Frequency score.1,2

The SAQ-generated categories of none, monthly, or daily/weekly angina were used to represent the patients’ reports of their angina frequency and the physicians’ documentation of angina frequency was used to quantify the physicians’ perceptions of angina frequency.1

References:

  1. Kureshi F et al. Clin Cardiol. 2017 January ; 40(1): 6–10.
  2. Arnold SV et al. Circ Cardiovasc Qual Outcomes. 2016 September;9(5): 554–559 doi:10.1161/CIRCOUTCOMES. 116.002781.

References:

  1. Guidelines 2024 on CCS management, Recommendation Table 16.
  2. Jackson, G., Combination therapy in angina, Int J Clin Pract., 2001;55(4):256-61.

References:

  1. Serruys PW, et al., N Engl J Med. 2001;344(15):1117-1124.
  2. Boden WE, et al., N Engl J Med. 2007;356(15):1503-1516.
  3. Cohen DJ, et al., N Engl J Med. 2011;364(11):1016-1026.
  4. Tonino PAL, et al., N Engl J Med. 2009;360:213-224.
  5. Dagenais GR, et al., Circulation. 2011;123(14):1492-1500.
  6. Holubkov R, et al., Am Heart J. 2002;144(5):826-33.
  7. Paolo I, et al,. Eur Heart J Acute Cardiovasc Care. 2012 Jun;1(2):158–169. doi: 10.1177/2048872612449111.

References:

  1. Kosiborod M. et al. JACC. 2013; 61 (20) 2038-45
  2. Ambrosio et al. Diabetes & Vascular Disease Research 2016, Vol. 13(2) 98–112

References:

  1. Chaitman B.R. et al. JAMA 2004; 291 (3): 309-316

References:

  1. Morrow D, et al., JAMA, 2007;297:1775-83.
  2. Wilson SR, et al., Adapted from Table 2 and Figure 1 in: J Am Coll Cardiol, 2009;53(17):1510-6.

References:

  1. Wilson SR, et al., Adapted from Table 2 and Figure 1 in: J Am Coll Cardiol, 2009;53(17):1510-6.

References:

  1. Villano A, et al. Am J Cardiol. 2013;112:8-13.

References:

  1. Tagliamonte E, et al. Echocardiography. 2015;32:516-21.

References:

  1. Tagliamonte E, et al. Echocardiography. 2015;32:516-21

References:

  1. Ling, H., et al. (2024). Ranexa for improving coronary microvascular function in nonobstructive CAD: A systematic review and meta-analysis. Quant Imaging Med Surg, 14(2), 1451–1465.
    https://doi.org/10.21037/qims-23-1029

References:

  1. Kosiborod M. et al. JACC. 2013; 61 (20) 2038-45.
  2. Ambrosio et al. Diabetes & Vascular Disease Research 2016, Vol. 13(2) 98–112.

References:

  1. Stone P.H. et al. J Am Coll Cardiol 2006; 48 (3): 566-575.

References:

  1. Morrow D, et al., JAMA, 2007;297:1775-83.
  2. Wilson SR, et al., Adapted from Table 2 and Figure 1 in: J Am Coll Cardiol, 2009;53(17):1510-6.

References:

  1. Alexopoulos D, et al., Int J Cardiol., 2016;205:111-6.

References:

  1. Chaitman B.R. et al. JAMA 2004; 291 (3): 309-316

References:

  1. Chaitman B.R. et al. JAMA 2004; 291 (3): 309-316

References:

  1. Borzi M et al. J Cardiovasc Med (Hagerstown). 2018 Apr;19(4):186-190

References:

  1. Borzi M et al. J Cardiovasc Med (Hagerstown). 2018 Apr;19(4):186-190

References:

  1. Modified from: Stone P, et al., J Am Coll Cardiol, 2006;48(3):566-75.

References:

  1. Morrow D, et al., JAMA, 2007;297:1775-83.
  2. Extrapolated from: Arnold SV, et al., Circ Cardiovasc Qual Outcomes, 2008;1(2):107-15.

References:

  1. Diedrichs H, et al., J Clin Exp Cardiolog 2015, 6:12.

References:

  1. Olympios C, et al., J. Clin. Med., 2024;13(6), 1672. https://doi.org/10.3390/jcm13061672.

References:

  1. Olympios C, et al., J. Clin. Med., 2024;13(6), 1672. https://doi.org/10.3390/jcm13061672.

References:

  1. Modified from: Hasenfuss G, Maier LS, Clin Res Cardiol, 2008;97:222-26.
  2. Sossalla S. Maier LS. Pharmacol Ther. 2012 Mar;133(3):311-23. doi: 10.1016.
  3. Belardinelli L et al. Heart 2006;92(Suppl IV):iv6–iv14.
  4. Keating GM. Drugs. 2013;73(1):55–73. doi:10.1007/s40265-012-0005-z.

References:

  1. Modified from: Hasenfuss G, Maier LS, Clin Res Cardiol, 2008;97:222-26.
  2. Sossalla S. Maier LS. Pharmacol Ther. 2012 Mar;133(3):311-23. doi: 10.1016.
  3. Belardinelli L et al. Heart 2006;92(Suppl IV):iv6–iv14.
  4. Keating GM. Drugs. 2013;73(1):55–73. doi:10.1007/s40265-012-0005-z.

References:

  1. Vrints, C., et al., 2019 ESC Guidelines for the management of chronic coronary syndromes, European Heart Journal, 2019.
  2. Vrints, C., et al., 2024 ESC Guidelines for the management of chronic coronary syndromes, European Heart Journal, 2024.
  3. Salim S. Virani et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation AHA. 2023.

References:

  1. Manolis AJ et al. Eur J Intern Med. 2020;72:5–8. doi:10.1016/j.ejim.2019.12.012.
  2. Knuuti J et al. European Heart Journal (2020) 41, 407477. doi:10.1093/eurheartj/ehz425.

Intensity of antianginal pharmacologic management for patients with frequent (daily/weekly) angina (n = 96)
(modified from fig. 2 of 1)

Mean number of anginal attack and weekly consumption of sublingual nitroglycerin with Ranexa in the TERISA study p < 0.01 for both comparisons
(modified from fig. 3 of 2)

Change in Treadmill Exercise Duration From Baseline at Trough Ranexa
Levels Over Time.

Data are least square means (SE). P-values are for comparisons
of each Ranexa group vs placebo (modified from fig. 2 of 1)

Change in Treadmill Exercise Duration From Baseline at Trough Ranexa
Levels Over Time.

Data are least square means (SE). P-values are for comparisons
of each Ranexa group vs placebo (modified from fig. 2 of 1)

Results of the SAQ and EuroQoL scale at baseline and follow-up in the groups of patients treated by ivabradine or Ranexa. P-values refer to comparisons of changes between the ivabradine group and the Ranexa group at follow-up compared with baseline, as derived by variable-group interaction analyses on repeated-measure ANOVA. Data are means ± SEM

Number of weekly angina attacks, excluding patients with weekly angina rate in the top 2% and bottom 2% of each treatment group (trimmed mean).

SE=standard error of the trimmed mean

(modified from fig. 3A of 1)

Mean number of anginal attack and weekly consumption of sublingual nitroglycerin with Ranexa in the TERISA study p < 0.01 for both comparisons (modified from fig. 3 of 2)

Change in Treadmill Exercise Duration From Baseline at Trough Ranexa Levels Over Time.

Data are least square means (SE). P-values are for comparisons

of each Ranexa group vs placebo (modified from fig. 2 of 1)

Prospective, multi-centre, observational, study with a 6-month follow-up and study visits at baseline, 3- and 6 months in patients (n=189) with chronic stable angina. Ranexa was administered according to the summary of product characteristics and investigator discretion. Primary objective: to evaluate tolerability, compliance, and perception of Ranexa effectiveness for chronic stable angina in a routine clinical setting.​

Start antianginal drugs at low doses in patients with low BP or HR, with preferential use of drugs with no or limited effects on BP or without heart rate-lowering effects.2


#Ranexa is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists);


*normal ejection fraction;

**heart rate > 70 bpm; BB = beta blocker; CCB = calcium channel blocker; DHP = dihydropyridine; SBP = systolic blood pressure; LANs = long acting nitrates. (modified from fig. 1 of 1)

The Angina Prevalence and Provider Evaluation of Angina Relief (APPEAR) was a cross-sectional, multicenter study designed to assess the frequency of angina and its impact on quality of life among 1257 outpatients with coronary artery disease across 25 US sites. Eligible patients had documented history of CAD and -1 prior office visit at the practice site. Angina was assessed directly from patients using the Seattle Angina Questionnaire Angina Frequency score.1,2


The SAQ-generated categories of none, monthly, or daily/weekly angina were used to represent the patients’ reports of their angina frequency and the physicians’ documentation of angina frequency was used to quantify the physicians’ perceptions of angina frequency.1

Potential Reasons for Persistent Angina7

  • Incomplete revascularization
  • Graft/PTCA failure
  • Disease progression
  • Spasm
  • Diffuse non-occlusive atherosclerosis
  • Microvascular dysfunction
  • Sub-optimal therapy

TERISA study: a randomized, double-blind, placebo-controlled trial in 949 patients with type 2 diabetes mellitus, coronary artery disease and stable angina treated with up to two anti-anginal agents. After a single-blind, 4-week placebo run-in patients were randomized to 8 weeks of double-blind Ranexa (target dose 1,000 mg* bid) or placebo. The primary efficacy endpoint was the mean weekly number of angina episodes over the last 6 weeks of the study.1


*In EU Ranexa is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.

CARISA study: a randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were randomly assigned to receive twice daily placebo or Ranexa 750 mg or 1,000 mg* of on top of background therapy. The primary aim of the study was to compare the effects of Ranexa vs placebo on treadmill exercise duration at trough Ranexa levels.1


*In EU Ranexa is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.

Pre-specified analysis of the antianginal efficacy and safety of Ranexa in the subgroup of 3,565 patients with a history of chronic angina who presented with an acute coronary syndrome (ACS) and were enrolled in the MERLIN–TIMI (Metabolic Efficiency with Ranexa for Less Ischaemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 trial. MERLIN–TIMI 36 trial was a multinational, randomized, double-blind, placebo controlled parallel group trial of Ranexa (1,000 mg* twice daily) in patients with a non–ST-segment elevation ACS. After 12 to 96 h of the intravenous formulation, study medication (Ranexa extended-release or placebo) was to be continued orally at a dose of 1,000 mg* twice daily until the end of the study. The primary efficacy end point of the trial was the first occurrence of any element of the composite of cardiovascular death, myocardial infarction (MI), or recurrent ischaemia and did not differ between Ranexa and placebo. End points specifically designed to assess the efficacy of Ranexa as antianginal therapy included worsening angina the need for an increase or addition of any antianginal therapy, and exercise duration on treadmill or bicycle ETT performed at 8 months (or final visit whichever was sooner).1

*In EU Ranexa is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.

Patients (n=46) with stable MVA (effort angina, positive exercise stress test, normal coronary angiography, coronary flow reserve <2.5), who had symptoms inadequately controlled by standard anti-ischaemic therapy, were randomised to ivabradine (5 mg BID), Ranexa (375 mg BID), or placebo for 4 weeks. The Seattle Angina Questionnaire (SAQ), EuroQoL (European Quality of Life) scale, and exercise stress test were assessed at baseline and after treatment.

SAQ items and EuroQoL VAS improved significantly in both ivabradine and Ranexa groups, whereas no changes were observed in group placebo. Comparisons of ivabradine and Ranexa groups showed that Ranexa achieved better results for several SAQ items and for the EuroQoL VAS.

Double-blind, placebo controlled trial. Fifty-eight patients with angina and evidence of myocardial ischemia, but no obstructive CAD, were assigned to Ranexa or placebo for 8 weeks (up to 500 mg twice a day). Coronary flow reserve and the Seattle Angina Questionnaire were assessed before and after 8-week therapy.

Double-blind, placebo controlled trial. Fifty-eight patients with angina and evidence of myocardial ischaemia, but no obstructive CAD, were assigned to Ranexa or placebo for 8 weeks (up to 500 mg twice a day). Coronary flow reserve and the Seattle Angina Questionnaire were assessed before and after 8-week therapy.1

Study Details

Method: A comprehensive meta-analysis of RCTs up to September 2023 utilized multiple databases and rigorous screening to assess outcomes using RevMan 5.4 and Stata 16.0, ensuring robust bias evaluation and heterogeneity analysis.


Conclusion: Ranexa shows potential in improving CFR, myocardial perfusion, and Seattle Angina Questionnaire scores in patients with nonobstructive coronary artery disease.

Ranexa is Recommended by AHA/ACC as an Add-in

Therapy for the Management Of Microvascular Angina1

INOCA endotype

Linked Pharmacotherapy

Microvascular angina

First line: Beta blocker

Second line: non DHP- CCB substituted where beta

blockers are not tolerated or ineffective.

Third line: Add-in therapy

CCB-DHP-only for those on beta blockers

Nicorandil* (unavailable in the USA)

Ranexa

ERICA study: stable patients (n = 565) with CAD and ≥3 attacks per week despite maximum recommended dosage of amlodipine (10 mg/day) were randomized to 1,000 mg* Ranexa or placebo twice a day for 6 weeks. Primary endpoint was the frequency of angina episodes per week during the double-blind treatment phase.1


*In EU Ranexa is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.

TERISA study: a randomized, double-blind, placebo-controlled trial in 949 patients with type 2 diabetes mellitus, coronary artery disease and stable angina treated with up to two anti-anginal agents. After a single-blind, 4-week placebo run-in patients were randomized to 8 weeks of double-blind Ranexa (target dose 1,000 mg* bid) or placebo. The primary efficacy endpoint was the mean weekly number of angina episodes over the last 6 weeks of the study.1


*In EU Ranexa is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina

CARISA study: a randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were randomly assigned to receive twice daily placebo or Ranexa 750 mg or 1,000 mg* of on top of background therapy. The primary aim of the study was to compare the effects of Ranexa vs placebo on treadmill exercise duration at trough Ranexa levels.1



*In EU Ranexa is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.

Pre-specified analysis of the antianginal efficacy and safety of Ranexa in the subgroup of 3,565 patients with a history of chronic angina who presented with an acute coronary syndrome (ACS) and were enrolled in the MERLIN–TIMI (Metabolic Efficiency with Ranexa for Less Ischaemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 trial. MERLIN–TIMI 36 trial was a multinational, randomized, double-blind, placebo controlled parallel group trial of Ranexa (1,000 mg* twice daily) in patients with a non–ST-segment elevation ACS. After 12 to 96 h of the intravenous formulation, study medication (Ranexa extended-release or placebo) was to be continued orally at a dose of 1,000 mg* twice daily until the end of the study. The primary efficacy end point of the trial was the first occurrence of any element of the composite of cardiovascular death, myocardial infarction (MI), or recurrent ischaemia and did not differ between Ranexa and placebo. End points specifically designed to assess the efficacy of Ranexa as antianginal therapy included worsening angina the need for an increase or addition of any antianginal therapy, and exercise duration on treadmill or bicycle ETT performed at 8 months (or final visit whichever was sooner).1


*In EU Ranexa is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.

Patients (n=46) with stable MVA (effort angina, positive exercise stress test, normal coronary angiography, coronary flow reserve <2.5), who had symptoms inadequately controlled by standard anti-ischaemic therapy, were randomised to ivabradine (5 mg BID), Ranexa (375 mg BID), or placebo for 4 weeks. The Seattle Angina Questionnaire (SAQ), EuroQoL (European Quality of Life) scale, and exercise stress test were assessed at baseline and after treatment.

SAQ items and EuroQoL VAS improved significantly in both ivabradine and Ranexa groups, whereas no changes were observed in group placebo. Comparisons of ivabradine and Ranexa groups showed that Ranexa achieved better results for several SAQ items and for the EuroQoL VAS.

Double-blind, randomised, placebo-controlled parallel group study . Patients (n=565) with stable angina receiving amlodipine 10 mg were randomised to Ranexa (500 mg bid increased to 1,000 mg bid, n=281) or placebo (n=284) for 7 weeks totally. The primary efficacy variable was the weekly average frequency of self-reported angina episodes during the 6-week double-blind full-dose treatment phase.

Study Design: The RANGER study was a non-interventional, prospective phase IV study evaluating Ranexa’s effectiveness, safety, and tolerability in stable AP patients across 214 sites in Greece.1


Study Population: Eligible patients were adults with stable AP who recently started Ranexa treatment. Of 1,101 enrolled, 73.3% were men, 27.7% were women, and 32.8% were diabetic. Mean age was 71.3 years.1

Ranexa has been shown to be a potent inhibitor of late INa and therefore interrupts a major step in the pathophysiology of myocardial ischaemia.1

Ranexa has been shown to be a potent inhibitor of late INa and therefore interrupts a major step in the pathophysiology of myocardial ischaemia.1

Tailored Approach

Last ESC Guidelines state that the initial choice of antianginal drug(s) depends on:2

  • The expected tolerance related to the individual patient’s profile and comorbidities
  • Potential drug interactions with co-administered therapies
  • Patient’s preferences after being informed of potential adverse effects
  • Drug availability