Patient profile based management approach for Optimal Treatment of Angina: a consensus from India cases

INTRODUCTION

Coronary artery disease (CAD) is one of the major health concerns for the Indian population. Worldwide, its prevalence has been steadily increasing, and India is no exception to this. Moreover, there is a rising incidence of CAD in the younger population in India.

In the contemporary clinical practice, we often interchangeably use stable ischemic heart disease (SIHD), stable CAD, and stable angina. However, stable angina is the symptomatic form of SIHD, whereas stable CAD is the pathology that may or may not be symptomatic.¹

Classically, the presence of substernal chest pain or discomfort lasting for less than 10 minutes has been described as angina pectoris. Angina may present as pain that may be referred to the arms or the jaw. An atypical presentation may include the complaints of discomfort, dyspnea, and diaphoresis.²

Emotional or physical stress or exercise can provoke this pain, which can be relieved by rest or nitroglycerin in patients who have stable angina.² These transient episodes of chest pain may occur over several weeks in cases of stable angina.³

Angina is the first symptom of CAD in nearly 50% of patients with SIHD. It was first described in 1772 by William Heberdeen.⁴ The most likely pathology is atheromatous CAD, which may be documented by various imaging techniques. Vasospasm and microvascular angina also form a part of the pathology for SIHD.³ Angina develops due to an inadequate coronary blood flow during the periods of an increased myocardial oxygen demand.⁴

It is estimated that nine million adults in the United States have chronic angina.4 India too has witnessed a rising prevalence of chronic angina that is subsequent to the increasing prevalence of CAD. The latter has increased from 1.1% to about 7.5% in the urban population and from 2.1% to 3.7% in the rural population.⁵ An early diagnosis and appropriate, immediate measures are necessary to reduce the morbidity and mortality associated with SIHD. However, clinical outcomes for patients with SIHD can vary greatly depending on patient characteristics.⁴ Some of these are commonly encountered in clinical practice. Few such common patient profiles for angina in the Indian scenario are discussed here to facilitate the clinical practice recommendations.

Objectives

The goal of OPTA is to assist clinicians with tools for the accurate diagnosis and prognosis of suspected angina and provide the patients with the optimum medical management in the Indian setting.

The key parameters to be addressed by a panel of experts included:

• • Symptomatic relief,
• • Delay in disease progression,
• • Building exercise capacity,
• • Improvement in QoL.

OPTA intended to develop the following tools to assist in meeting the above-mentioned goals: A prompt and accurate diagnosis of CSA, understanding of the symptomatology and presentation of a patient with angina, forming a treatment algorithm to manage CSA.

METHODS

In accordance with the above-mentioned objectives, ten regional board meetings were conducted across India. In all, more than 100 experts from the field of cardiology attended these meetings. The patient profiles commonly encountered in the Indian population and their management were discussed.

Common patient profiles

Case 1 - Chronic stable angina

History

A 65-year old man presented with progressively increasing, transient episodes of chest pain for the past 15 days; the pain would radiate to the left arm, occur with a routine activity, and be relieved by rest. The patient was a known case of CSA for the past 3 years and was on medical therapy for the same. He was also on treatment for hypertension for the past 6 years.

The patient had a family history of CAD; his father and elder brother both died due to myocardial infarction (MI) at the ages of 57 and 63 years, respectively, and his 38-year-old son had been diagnosed with hypercholesterolemia.

The patient was a tobacco chewer for the past 35 years and would consume alcohol (120-180 mL) 2-3 days in a week (Table 1).

The medication history was as follows:

Metoprolol succinate 25 mg twice daily, telmisartan 40 mg once daily, atorvastatin 40 mg once daily, aspirin 75 mg once daily, clopidogrel 75 mg once daily, Short-acting nitrate SOS for immediate relief from angina

Examination

On general examination, the BP was elevated at 138/94 mmHg, and the BMI was 30 kg/m². Systemic examination revealed no abnormality.

Investigations

Results of blood investigations were as follows (Table 2). Resting ECG showed sinus bradycardia with concentric left ventricular hypertrophy and severe type IV left ventricular diastolic dysfunction. The LVEF was 55%, and no regional wall motion abnormalities were observed with 2D echocardiogram. Exercise treadmill test (Bruce protocol) had to be stopped at 4.12 minutes, because the patient complained of moderate angina. Angiography revealed triple vessel disease with three stable lesions. One of the lesions showed 99%-100% block.

Management

Management of angina includes the treatment of risk factors to reduce the risk of future cardiac events. This can be achieved by lifestyle modifications, medical therapy, and surgery.

Lifestyle modification

• • Complete cessation of tobacco chewing needs to be ensured.
• • A nutritionist/dietician should be consulted for weight reduction in view of high BMI and dyslipidemia.

Pharmacotherapy

Optimization of therapy

Metoprolol succinate extended release 100 mg once daily, Telmisartan 40 mg once daily, Atorvastatin 40 mg once daily^@, Aspirin 75 mg once daily, Clopidogrel 75 mg once daily, Trimetazidine 60 mg once daily, Pantoprazole 40 mg once daily, Long-acting nitrate SOS (Figure 1 and Table 3). {^@With an increase in atorvastatin from 40–80 mg, 6% reduction in LDL-C is expected}.

Case 2 - Microvascular angina

History

A 61-year-old woman presented with the complaint of chest pain upon exertion for the past 3 months. The pain would radiate to the left arm and neck and was not associated with breathlessness or palpitations. The patient was a known case of diabetes mellitus for the past 10 years and hypertension for the past 15 years. Her father died of MI at the age of 67 years (Table 4).

Examination

The results of general and systemic examinations were normal.

Investigation

The troponin I level was normal (6.3 ng/mL). On the lipid profile, except for LDL-C (109 mg/dL), other levels were within normal limits. The liver function test was normal, eGFR was 67. 65 mL/min/1.73 m2, and serum creatinine was 1.1 mg/dL.

Resting ECG revealed ST-T changes.^$$ {^$$ Exercise ECG is not recommended in this case, Dobutamine stress test can be considered. In patients with osteoarthritis, cycling can be utilized instead of treadmill test (TMT)}. On angiogram, coronary arteries appeared normal. In patients with chronic effort angina due to left ventricular hypertrophy (LVH) with hypertension and diabetes with normal coronary arteries, the likely diagnosis was microvascular angina.

Management

Lifestyle modification

Consultation with a dietician: Increased consumption of fruits and vegetables and a low sodium intake, Cardiac rehabilitation with an exercise program (Table 5).

Pharmacotherapy

For diabetes

• • Metformin 500 mg twice daily
• • Teneligliptin 20 mg once daily
• • Pioglitazone 15 mg once daily (SGLT2 inhibitors are preferred over pioglitazone in patients with diastolic dysfunction)

For hyperlipidemia

Atorvastatin 40/80 mg once daily

For hypertension

• • Amlodipine 5 mg once daily
• • Olmesartan 20 mg once daily

For angina

• • Bisoprolol 2.5 mg once daily in the morning
• • Chlorthalidone 12.5 mg once daily
• • Trimetazidine 60 mg once daily
• • GTN 2.6 mg twice daily
• • Short-acting nitrates SOS

Case 3 - Angina in a woman

History

A 70-year-old woman presented with the progressive symptoms of chest pain along with palpitations, which would develop on walking and would be relieved by rest over the past 3 months. She reported a history of grade III dyspnea for the past 6 years. She was a known case of hypertension for the past 3 years and COPD for the past 6 years. Her mother and sister died due to MI at the age of 72 and 74 years, respectively. Her father was a patient with hypertension and had been receiving medications for it. She used to be a passive smoker for 36 years, because her husband was a chain smoker.

# Correction of anemia is very important; ## Normal values of D-dimer are less than or equal to 500 ng/mL. When a pulmonary event is suspected, it must be checked.

The patient was on amlodipine for the past 3 years and a salbutamol/formoterol combination inhaler. She was seeking a second opinion, because her coronary angiogram recorded at another hospital showed left main vessel disease (Table 6).

Chest discomfort remains the main symptom of angina. Women commonly present with atypical symptoms, and frequently they are inadequately treated. The presentation can be varied from patient to patient, such as: Uncomfortable pressure, squeezing, fullness, or pain in the center of the chest, Pain or discomfort in one or both arms, back, neck, jaw, or stomach, Shortness of breath with or without chest discomfort, Other signs, such as breaking out in a cold sweat, nausea, or lightheadedness. Symptoms may be subtle but consequences can be fatal, so they should not be ignored. Female patients may be under-/over-diagnosed, which can lead to a grave impact on prognosis.¹⁷

Examination

The patient had tachycardia; upon chest auscultation, rales were found. Rest of the examination was normal. Investigations as shown in Table 6 and 7.

Investigation

The ECG demonstrated left bundle branch block (LBBB).

The 2D ECHO showed a reduced LVEF (25%). The previous angiography showed 70% ostial stenosis. The intravascular ultrasound (IVUS) of the left main vessel showed a minimum lumen area of 6 mm² (Table 9).

Management

As the IVUS showed a minimum lumen area of 6 mm², optimal medical therapy was opted for instead of revascularization.

Pharmacotherapy

In such cases, transfusion should be avoided.

Iron + folic acid twice daily, Metoprolol 50 mg twice daily, Ramipril 5 mg twice daily, Ivabradine 5 mg twice daily$, Atorvastatin 40/80 mg once daily, Furosemide 20 mg once daily, Spironolactone 50 mg once daily, Continuation of the salbutamol + formoterol inhaler SOS. The husband of the patient was encouraged to quit smoking.

Role of ivabradine in CAD

Ivabradine does not unmask α-adrenergic vasoconstriction. Unlike β-blockers, it maintains coronary dilation during exercise. In comparison with β-blockers, ivabradine increases the coronary flow reserve and collateral perfusion, thereby promoting the development of coronary collaterals.²⁰ It also attenuates myocardial ischemia and its consequences even in the absence of heart rate reduction, possibly through the reduced formation of reactive oxygen species. Ivabradine is an effective antianginal and anti-ischemic agent for the treatment of CAD.^20,21 Ivabradine versus placebo for treatment in hospitalization for fatal and nonfatal MI in the patients with symptomatic angina.²¹

Case 4 - Chronic stable angina after a graft failure in diabetes mellitus

History

A 76-year-old man with a history of bypass surgery in 2005 presented for a follow-up. He gave a history of reduced effort tolerance (inability to climb staircases without taking frequent pauses).

The patient was a known case of diabetes, hypertension, and hyperlipidemia and was on medication for the same. There was a positive family history of diabetes, hypertension, and CAD. The patient would neither smoke nor consume alcohol.

The medication history included the following drugs:

Metformin 1,000 mg twice daily, Voglibose 0.2 mg thrice daily, Ramipril 5 mg twice daily*, Atorvastatin 20 mg once daily, Aspirin 75 mg once daily, Metoprolol 100 mg twice daily, Diltiazem extended release 180 mg once daily. [*Angiotensin-converting enzyme (ACE) inhibitors are preferred over angiotensin II receptor blockers (ARBs)].

Examination

The results of general and systemic examinations revealed no abnormality.

Investigation

The HbA1C value, fasting and postprandial blood glucose levels, and serum triglycerides were elevated. Results of 2D ECHO showed a mildly hypokinetic inferior basal wall of the left ventricle with an LVEF of 50%-55%.

Management

• • Lifestyle Modifications
• • Referral to a dietician for an appropriate diet to control risk factors and regular, light exercise
• • As the patient was unwilling for further intervention, medical therapy was opted.

Pharmacotherapy

For diabetes

• • Metformin 1,000 mg twice daily and
• • Voglibose replaced by empagliflozin 10 mg once daily in the morning (Table 4).

For hypertension

Ramipril replaced by telmisartan 80 mg once daily.

For hyperlipidemia

Atorvastatin dose increased to 40 mg once daily

For CAD

• • Aspirin 75 mg once daily,
• • Metoprolol 100 mg twice daily,
• • Diltiazem extended release 180 mg once daily and
• • addition of trimetazidine 60 mg once daily (Table 12).

DISCUSSION

The discussion section has been divided into evaluation and management of CSA.

Evaluation

The evaluation of CSA requires a detailed history and examination. The latter must include looking out for conditions that can increase the risk of atherosclerotic cardiovascular disease (AsCVD).

Extensive investigations include blood tests for hemogram, lipid profile, blood glucose testing, and liver and renal function tests.

Cardiac biomarkers form the important part of investigation to rule out ACS and heart failure. Whenever a pulmonary event is suspected, D-dimer testing must be included.

Resting ECG, which of normal, would be followed by exercise ECG. In cases with ST-T changes on resting ECG, further ECG testing is not required.

For patients with osteoarthritis, cycling instead of TMT can be considered and in patients who cannot perform exercise testing, dobutamine stress test/ Cardiac MRI must be considered. 2D ECHO should be performed in all patients.

Angiography should be done to review the coronary arteries, and FFR/IVUS should be performed to appropriately evaluate the case.

Management

Management comprises lifestyle changes, pharmacotherapy, and/or revascularization.

Lifestyle modification

Lifestyle changes are necessary for minimizing the influence of risk factors.

Based on the directions from the national committee consensus, the ultimate goals of medical management in patients with stable angina would include the following:

• • Alleviation of symptoms
• • Improvement in the effort tolerance
• • Improvement in the quality of life
• • Prevention of future adverse cardiac events

The European Society of Cardiology explains the multipronged approach toward the management of angina and the optimization of medical therapy to ensure successful outcomes.²⁹

The management for event prevention includes lifestyle modification and control of risk factors.

Pharmacotherapy

Antiplatelet drugs, statins, antianginal drugs, and ACEI/ARB form the armamentarium of pharmacotherapy. They are necessary for disease modulation.

Antiplatelet therapy

Aspirin is the prophylactic antiplatelet drug of choice, whereas DAPT may be considered for patients at a higher risk of a CV event.

Statins

High-intensity statins (atorvastatin 40-80 mg/ Rosuvastatin 20-40 mg) is needed.

Antianginal medications

Antianginal drugs

The 2013 European Society of Cardiology (ESC) guidelines recommend the addition of antianginal drugs, such as long-acting nitrates, ivabradine, nicorandil, trimetazidine, and ranolazine, to the first-line agents. Based on the pathophysiology and other contributing factors, the antianginal medications need to be individualized.

Based on the associated comorbidities, the preferable antianginal drugs and the less preferred choices have been described in Table 13.

Clinicians can evaluate their patients and plan the treatment accordingly by taking into consideration the various comorbidities described in Table 1.

Revascularization

Patients with CAD with significant stenosis (>50%) should be referred for revascularization. A detailed discussion on revascularization is beyond the scope of this statement.

Medical therapy may be continued with or without the revascularization procedures. For each case, a tailored management plan needs to be chalked out based on the evidence-based principles of the treatment described above.

CONCLUSION

This consensus statement was created to guide physicians in the evaluation and management of patients with stable angina. The newer approach, as advised by the ESC guidelines and by several supportive clinical studies and evidence, recommends a paradigm shift from the traditional approach of first-line and second-line agents to the consideration of different antianginal drugs and their combinations based on individual cases and associated morbidities.

ACKNOWLEDGEMENTS

Authors gratefully acknowledge the contribution of experts across India who gave their expert opinion in conceptualization and finalization of OPTA consensus in advisory board meetings.

Vinod Thomas, Anil Balachandran, Jubil P Mathew, Louie Fischer, N. Anil Kumar, Saji Subramanian, Arshad, Sheeba George, S S Binu, Praveen G K, Anup Kumar, Pradeep P, S V Praveen, Kathiresan, Karthickeyan, G Palanisamy, Jaishankar, Somasundaram, Mohana Murugan, Anand, P R Vaidhya Nathan, Sivabalan, Rajendran, Duraisamy, Thiyagarajan, Sarveshwaran, Kinjal Bhatt, Satyam Udhreja, Sharad Jain, Jay Shah, Rutvik Trivedi, Sanjay Vaghani, Anand Ahuja, Haresh Mehta, Mahesh Shah, Ashok Panjabi, Bharat Shivdasani, Dhiren Shah, Dayanand Kumbala, Brijesh Agrawal, Tushar Roy, A K Kheda, Anand Kumar Pandey, Sanjeev Sharma, Ashwani Mehta, Arun Mohanti, Gautam Swaroop, Ayush Shukla, Rajeev Rastogi, Sanjay Tandon, Rajesjh Jain, H S Shariq, Abhay Srivastav, P Mariappan, Omnath R, Srinivasan K.N, Krishnamurthy, S Nagendra Boopathy, Arumugam, V Magesh, V Murugesan, Latchumanadhas A, P Balaji, K P Shamsuddeen, J Ezhilan, S N Narasingan, D Prabakaran, S Guruprasad, Madhan Mohan, P Susheel Reddy, L Srichandran, K Chockalingam, Bivin Wilson, K A Sambasivam, S Socrates, A.L Narayanan, V Ramraj, S Manoj, P Manokar, M Karthik Anjaneyan, Dhamodharan, VE Dhandapani, RH Sundar, K P Suresh Kumar, K Mohan.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Pahlajani D. Management of stable ischemic heart disease - Current perspective. Available at: http://www.apiindia.org/pdf/medicine_update_2017/mu_202.pdf. Accessed Jun 12, 2018.
2. 2. Ohman EM. Clinical practice. Chronic stable angina. N Engl J Med. 2016 Mar 24;374(12):1167-76.
3. 3. Mishra S, Ray S, Dalal JJ, Sawhney JP, Ramakrishnan S, Nair T, et al. Management standards for stable coronary artery disease in India. Indian Heart J. 2016 Dec;68 Suppl 3:S31-S49.
4. 4. Kohan L, Annex BH. Clinical outcomes of patients with stable angina. Available at: http://www.acc.org/latest-in-cardiology/articles/2015/05/28/09/03/clinical-outcomes-of-patients-with-stable-angina. Accessed May 4, 2018.
5. 5. Sharma R, Bhairappa S, Prasad S, Manjunath CN. Clinical characteristics, angiographic profile and in hospital mortality in acute coronary syndrome patients in south Indian population. Heart India. 2014;2(3):65-69.
6. 6. Rao M, Xavier D, Devi P, Sigamani A, Faruqui A, Gupta R, et al. Prevalence, treatments and outcomes of coronary artery disease in Indians: A systematic review. Indian Heart J. 2015 Jul-Aug;67(4):302-10.
7. 7. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015 Nov 26;373(22):2103-16.
8. 8. Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017 Apr;23(Suppl 2):1-87.
9. 9. Riddle MC, Bakris G, Blonde L, Boulton AJM, D’ Alessio D, Groot MD, et al. For American Diabetes Association. Standards of medical care in diabetes-2018. Diab Care. 2018;41(Suppl 1):s1-s155.
10. 10. Degrauwe S, Pilgrim T, Aminian A, Noble S, Meier P, Iglesias JF. Dual antiplatelet therapy for secondary prevention of coronary artery disease. Open Heart. 2017 Oct 15;4(2):e000651.
11. 11. Dézsi CA. Trimetazidine in practice: Review of the clinical and experimental evidence. Am J Ther. 2016 May-Jun;23(3):e871-9.
12. 12. Banon D, Filion KB, Budlovsky T, Franck C, Eisenberg MJ. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. Am J Cardiol. 2014 Mar 15;113(6):1075-82.
13. 13. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators. Antianginal efficacy of ranolazine when added to treatment with amlodipine: The ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol. 2006 Aug 1;48(3):566-75.
14. 14. Camici PG, Olivotto I, Rimoldi OE. The coronary circulation and blood flow in left ventricular hypertrophy. J Mol Cell Cardiol. 2012 Apr;52(4):857-64.
15. 15. Ferrari R, Camici PG, Crea F, Danchin N, Fox K, Maggioni AP, et al. Expert consensus document: A 'diamond' approach to personalized treatment of angina. Nat Rev Cardiol. 2018 Feb;15(2):120-32.
16. 16. Nalbantgil S, Altintiğ A, Yilmaz H, Nalbantgil I I, Önder R. The effect of trimetazidine in the treatment of microvascular angina. Int J Angiol. 1999 Jan;8(1):40-3.
17. 17. Kreatsoulas C, Crea-Arsenio M, Shannon HS, Velianou JL, Giacomini M. Interpreting angina: Symptoms along a gender continuum. Open Heart. 2016 Apr 28;3(1):e000376.
18. 18. Garg P, Morris P, Fazlanie AL, Vijayan S, Dancso B, Dastidar AG. Cardiac biomarkers of acute coronary syndrome: From history to high-sensitivity cardiac troponin. Intern Emerg Med. 2017 Mar;12(2):147-55.
19. 19. Bay M, Kirk V, Parner J, Hassager C, Nielsen H, Krogsgaard K, et al. NT-proBNP: A new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function. Heart. 2003 Feb;89(2):150-4.
20. 20. Camici PG, Gloekler S, Levy BI, Skalidis E, Tagliamonte E, Vardas P, et al. Ivabradine in chronic stable angina: Effects by and beyond heart rate reduction. Int J Cardiol. 2016 Jul 15;215:1-6.
21. 21. Giavarini A, de Silva R. The role of ivabradine in the management of angina pectoris. Cardiovasc Drugs Ther. 2016 Aug;30(4):407-17.
22. 22. Tariq A, Zaman A. Management of stable angina in patients with type 2 diabetes mellitus. J Clin Prev Cardiol. 2014 Jul;3:73-84.
23. 23. Fearon WF, Nishi T, De Bruyne B, Boothroyd DB, Barbato E, Tonino P, et al. Clinical outcomes and cost-effectiveness of fractional flow reserve-guided percutaneous coronary intervention in patients with stable coronary artery disease: Three-year follow-up of the FAME 2 trial. Circulation. 2018 Jan 30;137(5):480-7.
24. 24. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-89.
25. 25. Mosleh W, Sharma A, Sidhu MS, Page B, Sharma UC, Farkouh ME. The role of SGLT-2 inhibitors as part of optimal medical therapy in improving cardiovascular outcomes in patients with diabetes and coronary artery disease. Cardiovasc Drugs Ther. 2017 Jun;31(3):311-8.
26. 26. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. 2012. ACCF/AHA/ACP/AATS/PCNA/SCAI/STS-Guideline for the diagnosis and management of patients with stable ischemic heart disease: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012 Dec 18;126(25):e354-471.
27. 27. Lipid-modifying drugs. Available at: https://www.nice.org.uk/advice/ktt3/chapter/evidence-context. Accessed Jun 12, 2018.
28. 28. Fragasso G, Piatti Md PM, Monti L, Palloshi A, Setola E, Puccetti P, et al. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J. 2003 Nov;146(5):E18.
29. 29. Ambrosio G, Mugelli A, Lopez-Sendón J, Tamargo J, Camm J. Management of stable angina: A commentary on the European Society of Cardiology guidelines. Eur J Prev Cardiol. 2016 Sep;23(13):1401-12.