Editorial

Graham Jackson
Consultant Cardiologist, Guy’s and St Thomas’ Hospitals NHS Trust,
Cardiothoracic Centre, St Thomas’ Hospital, London, UK

Correspondence: Dr Graham Jackson, Guy’s and St Thomas’ Hospitals NHS Trust, Cardiothoracic Centre, 6th Floor East Wing, St Thomas’ Hospital, Lambeth Palace Road,
London SE1 7EH, UK. Tel: +44 20 7928 9292, fax: +44 20 7960 5680
e-mail: lilian.crossley@gstt.sthames.nhs.uk

Refractory angina is defined as severe disabling angina in spite of optimal medical therapy and where percutaneous intervention or coronary artery surgery is not feasible. It is equivalent to class III or IV of the Canadian Cardiovascular Society classification [1].
As both percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) are effective in relieving symptoms [2], these options should have been excluded by experienced interventional cardiologists or cardiac surgeons, and their decision based on a recent coronary angiogram, preferably performed within the preceding 3 months. This may seem to be self-evident, but in a study evaluating transmyocardial laser revascularization, 72 (62%) of 117 patients initially referred because of refractory angina responded to changing their medical therapy (44%) or intervention by PTCA or CABG (18%) [3]. As long ago as 1975 [4], the problem of suboptimal medical therapy was highlighted and it has been the focus of recent reviews [2, 5].
Establishing that angina is truly refractory to conventional therapy requires a detailed evaluation of each individual patient, the nature of their symptoms (is it really angina?), and the exclusion of secondary causes [6]. We must also be sure that they are taking their medication in the doses prescribed, and that the prescribed medication has been optimized for the individual concerned.
Whilst coronary artery disease (CAD) is clearly the commonest cause of angina, the symptoms may be exacerbated by other factors.
– If the patient is hypertensive, has the blood pressure been controlled effectively to a target of 140/90 mm Hg or less [7], and have the preferred agents for coexisting angina and hypertension (b-blockers and calcium antagonists) been utilized?
– Has anemia been ruled out?
– Is there any evidence of significant aortic valve disease? If in doubt, an echocardiogram will clarify and also give important information on left ventricular function.
– Is there evidence of rapid or slow arrhythmias (especially atrial fibrillation in the elderly)? Either may render angina difficult to control.
– Has thyrotoxicosis been ruled out?
When treating refractory angina, we must be clear that the symptoms reflect ischemia and we must have ruled out exacerbating causes. Patients usually have diffuse CAD affecting all major coronary arteries and may have undergone unsuccessful CABG or PTCA (see the case report in this issue). Unlike cardiac failure, the patient with refractory angina may not have substantially impaired left ventricular function.

General measures [8]
– Cigarette-smoking should stop, as cessation may improve symptoms and will improve prognosis.
– Obesity should be corrected with the help of a qualified dietitian and, if necessary, a course of carefully supervised drug therapy.
– Physical activity should be encouraged. Although exercise in these patients is likely to be very limited, it does help with weight loss and may reduce ischemic symptoms.
– Patients may be anxious about their condition and/or depressed. Relaxation techniques, specific counseling and antidepressant therapy may be helpful in reducing the adverse impact of psychological factors on symptoms.

Compliance
Many patients do not take their medication, or take it incorrectly. They may stop their medication because of depression. Complex regimes may be too demanding and create a feeling of helplessness in the patient.
Written material providing details of how to use medication correctly, counseling the patient and their closest relative (usually spouse), treating depression, and emphasizing the positive aspects of the therapy may enhance adherence to therapy [9].

Refractory angina: key questions
– Is it ischemic pain?
– Have precipitating causes been excluded?
– Is the patient taking the medication?
– Is the medication at an optimal dosage?
– Have PTCA and CABG been discussed with experienced operators?
– Has a combination of a hemodynamic and metabolic agent been tried?
– Have research protocols been explored?
– Have the psychosocial aspects been addressed?

Management
After asking several key questions, listed above, a practical strategy needs to be adopted. In this issue of Heart and Metabolism the important aspects of management are considered. Dr Paolo Camici discusses the role of positron emission tomography as a noninvasive means of defining viable myocardium which is relevant to the management of refractory pain. Interestingly, he concludes that transmyocardial laser revascularization may reduce angina but not by improving perfusion or coronary reserve in the lasered areas. This raises important issues about pain perception which is comprehensively covered by Dr Robert Foreman. He highlights the huge variations in perception which, while currently undergoing detailed study, leave us at present with the difficulties of individualized care with regard to response to therapy. The evaluation and mechanism of cardiac ischemic pain are covered from a different perspective by Professor Filippo Crea and Dr Achille Gaspardone who again point out how elusive the connection is between objective evidence of myocardial ischemia and cardiac ischemic pain.
We can clearly see the difficulties in management because of the lack of direct objective evidence of ischemia in relationship to the clinical endpoint of pain. Dr Duncan McNab and Dr Peter Schofield explore new therapeutic approaches, focusing on mechanical means of pain relief, and providing a comprehensive and very useful overview. However, once more the mechanisms of benefit remain unclear. Dr M. Chester provides us with a clinical assessment which alerts us to the need for a comprehensive strategy given that the incidence and prevalence of refractory angina will increase within the next decade.
Incorporating a metabolic approach with trimetazidine may be in part preventative, as discussed by Dr Holban, but importantly it offers a different evidence-based approach to improving the quality of life of those disabled by chronic cardiac pain [10]. My case report illustrates its potential. Refractory angina is a time-consuming management problem with a deleterious psychosocial impact on quality of life, requiring counseling and support to the patient and close relatives or friends. This means the approach must be multidisciplinary, involving specialized nurses and health care workers, both in the hospital and the community.

REFERENCES 

1: Circulation 1976 Sep;54(3):522-3 Related Articles, Books, LinkOut

Letter: Grading of angina pectoris.

Campeau L.

PMID: 947585 [PubMed - indexed for MEDLINE]
 
2: Eur Heart J 1997 May;18 Suppl B:B2-10 Related Articles, Books, LinkOut

Stable angina: drugs, angioplasty or surgery?

Jackson G.

Guy's Hospital, London, U.K.

Stable angina is a common condition with a good overall prognosis and annual mortality is 2-4%, whatever treatment is employed. Medical therapy with nitrates, beta-blockers, calcium antagonists and lipid-lowering agents is appropriate as first-line therapy in those patients not specifically identified as being at risk by exercise testing and/or angiography. Dosage should be optimized. Coronary artery bypass grafting appears to improve prognosis in those at risk when compared with medical therapy but the trials are old and do not take into account major advances in medical therapy nor the use of arterial conduits in coronary artery bypass grafting (CABG). Percutaneous transluminal coronary angioplasty (PTCA) relieves symptoms when medical therapy is ineffective but its role as an initial therapy has not been established, nor does it compare favourably with CABG with regard to the degree of revascularization and subsequent re-intervention or need for additional anti-anginal drugs. There are little substantial data on prognostic effects. PTCA is, however, less traumatic, less expensive and associated with a quicker recovery than CABG, providing a viable alternative for symptomatic (not prognostic) benefit in appropriately selected and informed patients. Medical therapy, PTCA and CABG should not be seen as competitive but complementary strategies. Optimal utilization of all three treatment modalities, either alone or in combination, can provide substantial symptomatic relief for the angina patient.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 9152663 [PubMed - indexed for MEDLINE]

 
3: Z Kardiol 1997 Mar;86(3):171-8 Related Articles, Books, LinkOut

[Transmyocardial laser revascularization--a treatment option for coronary heart disease?]

[Article in German]

Nagele H, Kalmar P, Lubeck M, Marcsek P, Nienaber CA, Rodiger W, Stiel GM, Stubbe HM.

Abteilung fur Thorax-, Hertz- und Gefasschirugie Universitats-Krankenhaus Hamburg-Eppendorf.

Transmyocardial laser revascularization (TMR) is a new therapeutic principle for patients with coronary artery disease and no possibility of conventional revascularization with CABG or PTCA. The clinical value of the method is not known. Therefore we investigated all 46 patients treated with sole TMR in our center using clinical investigation, LV and coronary angiography, right heart catheterization, MIBI perfusion imaging and myocardial FDG-PET pre- and 6 months post TMR. 117 patients judged not suitable for conventional revascularization procedures were submitted for TMR. The indication for the procedure was reevaluated in every case. 52 patients (mean EF 41 +/- 16%) could be further treated by intensified anti-anginal medication, seven patients received bypass grafts, four patients had PTCA, three patients were listed for heart transplantation, and five patients had a combined CABG plus TMR. Only 46 (38% of the submitted patients, mean EF 55 +/- 15%) were accepted for sole TMR. CCS class of these patients was 3.3 +/- 0.4, mean age was 63.6 +/- 7.3 years, 70% were males. The postoperative mortality within 30 days was 5/46 (10.8%); 9/46 patients (19.5%) suffered from perioperative myocardial infarction. Other complications were ventricular fibrillation in two cases on the second postoperative day and a rupture of the spleen on the 14th postoperative day. 8/46 patients (17%) had wound infections. Survivors showed an improvement in their CCS class (1.9, 2.1, 1.9 after 3, 6 and 12 months, respectively, mean observation time 0.61 +/- 0.4 years). These patients were able to perform bicycle stress tests significantly longer (98 s +/- 9 pre versus 120 +/- 13 s post TMR, p = 0.01). Angiographic EF fell from 57.8% +/- 15% to 52.6% +/- 19% (p = 0.02) and the number of hypokinetic chords rose from 23.6 +/- 20.9% to 30.6 +/- 24.1% per patient (p = 0.008), predominantly in the inferior wall. Nuclear studies showed reduced myocardial perfusion and vitality after TMR. Four patients in the TMR group had reintervention (PTCA) because of progression of coronary sclerosis of native vessels. One patient had mitral valve replacement due to severe regurgitation. Kaplan-Meier analysis showed no significant difference in survival between the TMR and the medical group when stratified according to initial ejection fraction. Sudden death and congestive heart failure are the most important causes of mortality. Our data show that TMR improves symptoms and exercise performance of otherwise not treatable patients with diffuse coronary artery disease. Due to a lack of an improvement of cardiac perfusion, function or prognosis TMR should be used only in highly selected cases when conventional methods fail to improve patients symptoms.

PMID: 9173706 [PubMed - indexed for MEDLINE]
 
4: Br Med J 1975 Sep 13;3(5984):616-8 Related Articles, Books, LinkOut

Reassessment of failed beta-blocker treatment in angina pectoris by peak-exercise heart rate measurements.

Jackson G, Atkinson L, Oram S.

Twenty-one patients with angina pectoris were treated with adrenergic beta-receptor antagonists. Previously the resting heart rate had been used as a guide to treatment, a reduction in the rate to 55-60 beats/min without symptomatic improvement indicating failure of medical treatment. These patients were re-evaluated before coronary arteriography using the peak-exercise heart rate as an index of adrenergic beta-receptor antagonism. The dose of beta-blocking drugs was increased to produce a peak-exercise heart rate of less than 100 beats/min or a consistent rate of 100-125 beats/min which would not lessen in spite of progressive dose increments. The resting heart rate was ignored. On these criteria 15 patients previously considered to have responded inadequately to beta-blockade responded satisfactorily and were therefore removed from the waiting list for coronary arteriography. They all remained well up to two years later. Six patients failed to respond and had coronary arteriography with a view to surgical treatment. Reliance on the resting heart rate as the index of optimum adrenergic beta-receptor antagonism is likely to lead to premature or unnecessary referral for surgery; the failure of beta-blockade in the treatment of angina pectoris can be determined simply and accurately by using peak-exercise heart rate.

PMID: 240479 [PubMed - indexed for MEDLINE]
 
5: Am Heart J 1997 Oct;134(4):587-602 Related Articles, Books, LinkOut
Click here to read
Refractory angina pectoris in end-stage coronary artery disease: evolving therapeutic concepts.

Schoebel FC, Frazier OH, Jessurun GA, De Jongste MJ, Kadipasaoglu KA, Jax TW, Heintzen MP, Cooley DA, Strauer BE, Leschke M.

Heinrich-Heine University Dusseldorf, Clinic for Cardiology, Pneumonology, and Angiology, Germany.

Refractory angina pectoris in coronary artery disease is defined as the persistence of severe anginal symptoms despite maximal conventional antianginal combination therapy. Further, the option to use an invasive revascularization procedure such as percutaneous coronary balloon angioplasty or aortocoronary bypass grafting must be excluded on the basis of a recent coronary angiogram. This coronary syndrome, which represents end-stage coronary artery disease, is characterized by severe coronary insufficiency but only moderately impaired left ventricular function. Almost all patients demonstrated severe coronary triple-vessel disease with diffuse coronary atherosclerosis, had had one or more myocardial infarctions, and had undergone aortocoronary bypass grafting (70% of cases). We present three new approaches with antiischemic properties: long-term intermittent urokinase therapy, transcutaneous and spinal cord electrical nerve stimulation, and transmyocardial laser revascularization.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 9351724 [PubMed - indexed for MEDLINE]

 6. Jackson G. Angina. 2nd ed. London, England: Martin Dunitz; 1995.
 

7: Lancet 1998 Jun 13;351(9118):1755-62 Related Articles, Books, LinkOut

Comment in:

Click here to read
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.

Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S.

University of Uppsala, Department of Public Health and Social Sciences, Clinical Hypertension Research, Sweden.

BACKGROUND: Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension. METHODS: 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo. FINDINGS: Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001). INTERPRETATION: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 9635947 [PubMed - indexed for MEDLINE]

 
8: Eur Heart J 1997 Mar;18(3):394-413 Related Articles, Books, LinkOut

Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology.

Publication Types:
  • Guideline
  • Practice Guideline
  • Review
  • Review, Tutorial


PMID: 9076376 [PubMed - indexed for MEDLINE]

9. Gidron Y. Adherence in hypertension and coronary heart disease. In: Myers LB, Midence K, eds. Adherence to Treatment in Medical Conditions. Amsterdam, the Netherlands: Harwood Academic Publishers; 1998:473–496.
 

10: Int J Clin Pract 2001 May;55(4):256-61 Related Articles, Books, LinkOut

Combination therapy in angina: a review of combined haemodynamic treatment and the role for combined haemodynamic and cardiac metabolic agents.

Jackson G.

Cardiothoracic Centre, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.

The 1997 European Society of Cardiology guidelines emphasised medical therapy as the mainstay of treatment of stable angina. Until recently, the antianginal drugs available to control symptoms (nitrates, beta-blockers and calcium antagonists) have all been haemodynamic agents that eliminate or reduce angina attacks principally by decreasing myocardial oxygen demand. They may also improve myocardial perfusion. The haemodynamic agents are often used in combination. However, there is conflicting evidence for the efficacy of combination treatment. Two recently published large clinical studies, the Total Ischaemic Burden European Trial (TIBET) study and the International Multicenter Angina Exercise (IMAGE) study, suggest that combined haemodynamic treatment is no more effective than optimal monotherapy. The results from IMAGE suggest that most of the additional effect observed with combined therapy was attributable to recruitment by the second drug of patients who had not responded to monotherapy, and that most patients continued to have a disturbing frequency of anginal attacks after receiving combined therapy. Metabolic agents are a new class of drugs that directly modify the use of energy substrates in the heart, lessening ischaemic injury and improving cardiac performance during ischaemia. Due to their non-haemodynamic mode of action, metabolic agents such as trimetazidine or L-carnitine may provide independent benefit in ischaemia when used as monotherapy or additional benefit when used in combination with a conventional agent. Clinical trials have shown that combined haemodynamic and metabolic treatment is more effective than combined haemodynamic therapy and is well tolerated. It is suggested that combination haemodynamic and metabolic therapy is a logical new approach to patients whose angina is inadequately controlled despite optimal haemodynamic therapy.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 11406911 [PubMed - indexed for MEDLINE]

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