Management of Microvascular Angina Pectoris

Gaetano A. Lanza; Rossella Parrinello; Stefano Figliozzi

Disclosures

Am J Cardiovasc Drugs. 2014;14(1):31-40. 

In This Article

Treatment of Microvascular Angina (MVA)

As the occurrence of major cardiac events does not seem to be significantly increased in patients with MVA, the main goal of medical treatment is the control of symptoms and improvement in quality of life. Accordingly, studies in medical literature focused on these endpoints, whereas there are no data about whether treatment of primary MVA may have any effects on hard endpoints (e.g., cardiac death, acute myocardial infarction, or impairment of left ventricular function).

As in obstructive CAD, classical anti-ischemic drugs are the initial form of treatment, but their efficacy is often limited, even when given in combination. Accordingly, several alternative forms of therapy have been proposed for unresponsive patients, most of which are aimed to improve CMVD and myocardial ischemia, whereas a few others may directly act on pain transmission.

In examining therapeutic studies in MVA patients, it should be highlighted that they present several limitations, variably including the existence of only a few trials, the enrolment of a small number of patients, the lack of appropriate controls, the use of different endpoints, and assessment over only short-term follow-up. Accordingly, the degree of the efficacy of most therapies is far from being clearly defined.

5.1 Classical Anti-ischemic Drugs

5.1.1 β-Blockers. β-Blockers improve myocardial ischemia by reducing myocardial oxygen consumption, particularly during conditions characterized by increased sympathetic activity, such as exercise and stressful situations. However, they may also increase CBF by prolonging diastolic time and improving left ventricular dynamics. β-Blockers can be particularly useful in patients with evidence of increased sympathetic activity: a high basal heart rate, a rapid increase of heart rate and/or blood pressure during exercise, or a reduced heart rate variability.

Among β-blockers, atenolol (50/100 mg/die) was concordantly found to improve symptoms in a few studies, as compared with placebo or other drugs.[28–30] Accordingly, atenolol should constitute the preferred agent in these patients, as it is not known whether comparable effects on symptoms can be obtained with other β-blockers, even considering that atenolol,[30] but not some other bblockers,[31,32] were found to improve exercise stress test results in MVA patients.

5.1.2 Calcium Antagonists. Calcium antagonists might improve microvascular ischemia through dilation of dysfunctional resistance coronary arteries, but also by reducing cardiac afterload and blood pressure; furthermore, non-dihydropyridine drugs also reduce myocardial oxygen consumption due to their negative chronotropic and inotropic effects. However, calcium antagonists, particularly dihydropyridines,[33] may cause a reflex sympathetic activation, which may antagonize their favorable effects.

Calcium antagonists have been reported to reduce angina episodes in MVA patients in most [34–36], although not all,[29] studies; furthermore, significant effects have been reported on exercise-induced angina and ST-segment depression.[31,32,34–37] However, verapamil failed to reduce spontaneous episodes of ST-segment depression during daily life.[38] Finally, discordant results have also been reported about the effects of calcium antagonists on CBF.[36,39]

On the whole, data suggest that non-dihydropyridine calcium antagonists constitute a valid therapeutic first-line option, as an alternative to β-blockers, particularly in patients in whom the prevailing mechanism of angina appears to be increased microvascular constriction, i.e., patients who also report angina at rest or those who present slow coronary flow at angiography.[39] Dihydropyridine drugs can more usually be added as an additional antiischemic therapy to β-blockers.

5.1.3 Nitrates. The anti-ischemic effects of nitrates mainly rely on a reduction of cardiac pre-load mediated by peripheral venous dilation. However, nitrates also have coronary dilator effects, but the latter have been found to be limited in coronary microcirculation.[40]

Accordingly, while short-acting nitrates can be used to relieve angina attacks in MVA patients, their efficacy in this context is lower than in other forms of angina, with full effect being achieved in only about one half of patients[5] (see above).

Unexpectedly, the effects of chronic oral nitrate therapy in MVA patients have only been assessed in a small shortterm study in which isosorbide-5-mononitrate (40 mg) failed to improve symptoms over a period of 4 weeks.[29] Accordingly, nitrates cannot be recommended as a first-line therapy, although they are often added to β-blockers and/or calcium antagonists on an empirical basis.

5.2 Additional Anti-ischemic Drugs

A summary list of alternative drugs with potential antiischemic effects proposed for MVA patients who continue to present angina episodes despite optimal classical antiischemic therapy is shown in Table 1 .

5.2.1 Ranolazine. Ranolazine is a relatively new drug that exerts its antiischemic effect by inhibiting the inward late Na? current in cardiomyocytes; this results in a reduction of intracellular Ca2? inflow during ischemia, with improvement of myocardial relaxation and ventricular diastolic function. Of note, recent data suggest that ranolazine may improve endothelial function.[41] In clinical trials, ranolazine improved symptomatic state and exercise performance in angina patients with obstructive CAD.[42]

In a recent study, we randomized 45 patients with MVA with symptoms not satisfactorily controlled by standard medical therapy to receive ranolazine, ivabradine, or placebo for 4 weeks. Ranolazine, but not placebo, significantly improved angina symptoms and quality of life, as well exercise stress test results. Of note, the improvement was also significantly greater for several endpoints with ranolazine than with ivabradine (Fig. 2).[43]

Figure 2.

Effect of ranolazine and ivabradine in patients with microvascular angina (modified from Villano et al. [43])

The results of our study are in agreement with those of a crossover trial of 20 women with chest pain and normal coronary arteries, in whom angina symptoms were improved by ranolazine in the subgroup showing a reduced myocardial perfusion reserve.[44]

5.2.2 Ivabradine. Ivabradine is also a relatively novel anti-ischemic drug, which has been shown to improve angina symptoms in several clinical trials of patients with obstructive CAD.[45] Ivabradine is a pure bradycardic agent that acts by reducing pacemaker activity of the sinus node through inhibition of the If current, thus resulting in a reduced myocardial oxygen consumption both at rest and during exercise.

In our study,[43] ivabradine significantly improved angina status in MVA patients, compared with placebo, although its effects were lower than those found with ranolazine (Fig. 2).

5.2.3 Xanthine Derivatives. Xanthine compounds may reduce effort-related myocardial ischemia by favoring redistribution of CBF towards ischemic myocardial regions. Indeed, they may cause constriction in non-dysfunctional coronary microvessels through inhibition of both the dilator effect of adenosine and the re-uptake of norepinephrine by sympathetic nerve endings, thus facilitating CBF towards myocardial areas with CMVD.[46] Furthermore, by antagonizing adenosine, which is a major mediator of ischemic pain,[47] xanthines may also exert an 'analgesic' effect.

A few small studies have reported beneficial effects of the administration of a single intravenous or oral dose of xanthines (aminophylline, bamifylline) on exerciseinduced angina and/or ischemic ECG changes.[48–51]

In a small controlled study, oral administration of aminophylline (225–350 mg twice daily) for 3 weeks failed to significantly improve angina episodes, as well as signs of myocardial ischemia during exercise test and ECG Holter monitoring.[52]

Thus, the utility of xanthine compounds in MVA remains questionable and would need further assessment.

5.2.4 Angiotensin-converting Enzyme (ACE) Inhibitors. Angiotensin-converting enzyme (ACE) inhibitors might improve MVA through several potential favorable effects on coronary microcirculation, including microvascular dilatation, reduced oxidative stress, increased availability of nitric oxide and modulation of sympathetic nervous system activity related to the reduction of serum and tissue angiotensin II.

Beneficial effects on angina symptoms have been reported in small randomized controlled trials with ramipril, alone[35] or in combination with atorvastatin,[53] and quinapril has also been reported to improve angina status in a more heterogeneous population of women with normal coronary arteries and non-significant stenosis (<50 %).[54] Furthermore, in other studies, ACE inhibitors were found to increase exercise tolerance [55,56] and coronary microvascular function.[57]

Accordingly, ACE inhibitors should be taken into account for MVA patients, particularly in the presence of arterial hypertension.

5.2.5 α-Antagonist Drugs α-Blocking agents have been proposed for treatment of MVA due to their capacity to contrast α-mediated sympathetic constriction of small coronary arteries. However, on the whole, results have been disappointing. Doxazosin, a post-synaptic α-1 receptor blocker, improved coronary flow reserve (CFR) in an uncontrolled study,[58] but this effect was not confirmed in a controlled trial.[59] Similarly, no significant effects were observed with prazosin in another study.[60]

Tolerance can be a major limiting factor with α-blocking agents, which cannot be recommended at present as preferential additional drugs in MVA.

5.2.6 Nicorandil. Nicorandil has direct dilator effects on coronary resistance vessels due to adenosine triphosphate (ATP) potassium channel opening and nitrate-like effects. Nicorandil has been shown to improve symptoms, myocardial perfusion, and signs of myocardial ischemia in MVA patients.[61,62] Accordingly, although larger studies with adequate follow-up are necessary, this drug, where available, should be taken into account in the treatment of these patients.

5.2.7 Trimetazidine. Trimetazidine has been suggested to improve tolerance to myocardial ischemia by switching cell metabolism from free fatty acid towards glucose oxidation.

Trimetazidine has shown discordant results in patients with MVA. In a placebo-controlled study, the drug did indeed improve exercise capacity and time to 1 mm STsegment depression.[63] However, in another controlled trial, trimetazidine failed to achieve significant clinical effects.[30]

5.2.8 Statins. Statins have pleiotropic beneficial effects on vascular function, including anti-oxidant and anti-inflammatory properties, together with cholesterol-lowering effects, all of which result, in particular, in improvement of endothelial function.

In small randomized trials, simvastatin and pravastatin have been shown to improve endothelial function and exercise-induced myocardial ischemia in MVA patients with mild hypercholesterolemia, compared with controls.[64,65] Furthermore, a combination of ramipril and atorvastatin[53] improved quality of life and exercise tolerance, as compared with placebo, in these patients over a 6-month period.

Thus, data suggest that statins can be useful in MVA patients, particularly in those with high cholesterol levels or evidence of incident inflammatory activity and/or oxidative stress.

5.2.9 Estrogens. A significant number of patients with stable MVA are perimenopausal women,[24] suggesting that estrogen deficiency can be an important pathogenetic factor for the syndrome. Indeed, estrogen deficiency is associated with impaired endothelial function and increased adrenergic activity, typically present in MVA patients.[18,66] Transdermal 17-β-estradiol has been shown to reduce angina episodes in post-menopausal women with MVA in a placebo-controlled cross-over study,[67] and to improve exercise-induced angina and ST-segment depression in another study.[68]

Thus, estrogens can be helpful in the management of peri-menopausal women with MVA, although the initial benefits may decrease over long-term treatment;[69] furthermore, it is necessary to address some safety concerns about long-term administration.[70]

5.3 Pain-Inhibiting Drugs

Drugs able to inhibit transmission and processing of visceral pain might be helpful in patients with MVA resistant to anti-ischemic treatment, particularly when an enhanced painful perception of cardiac stimuli is present.[22,23]

The pain inhibitor imipramine has been assessed in two controlled trials. In a first study on patients with chest pain and normal coronary arteries, the drug reduced chest pain attacks by 52 ± 25 % over a period of 3 weeks,[71] whereas no significant effects were observed with placebo or clonidine. This effect of imipramine on angina episodes was confirmed in a second trial including typical MVA patients;[72] however, it failed to improve quality of life, likely due to a significant occurrence of side effects. Thus, although imipramine seems useful to prevent episodes of chest pain, the frequent occurrence of side effects can significantly limit its use.

5.4 Non-Pharmacological Treatments

Despite the wide availability of anti-angina drugs, in some cases chest pain episodes may persist and continue to upset MVA patients. In these cases of 'refractory MVA', some alternative non-pharmacological approaches have been proposed ( Table 2 ).

5.4.1 Spinal Cord Stimulation. Spinal cord stimulation (SCS) consists of the electrical stimulation of the dorsal horns of the spinal cord at C7-T1 level by a multipolar electrode catheter, which is introduced in the epidural space through an intervertebral puncture and is connected to a programmable pulse generator, usually implanted in a subcutaneous abdominal or gluteal pocket. SCS seems to exert its anti-angina effects through both direct modulation of cardiac pain transmission and improvement of myocardial ischemia, which is achieved through modulatory effects of sympathetic nerve activity.[73]

SCS in MVA patients has been shown to improve the ischemic and angina threshold, as well as exercise tolerance and spontaneous ischemic episodes.[74–76] Furthermore, long-term beneficial effects on angina episodes, nitrate consumption, and quality of life have been reported in a controlled study.[77] Accordingly, SCS should be considered in MVA patients refractory to various forms of medical therapy.

5.4.2 Enhanced External Counterpulsation. Enhanced external counterpulsation (EECP) consists of a sequential beat-by-beat distal to proximal inflation (in diastole) and deflation (in systole) of three pneumatic cuffs applied to the patient's legs. This results in increased diastolic coronary perfusion pressure, which seems to improve coronary endothelial function.[78] In a study of 30 patients with refractory MVA, EECP has been shown to improve angina status and myocardial ischemia.[79] However, controlled studies are needed to better define the role of EECP in these patients, also considering that the treatment cannot be tolerated by some patients and can be associated with some unwanted side effects (e.g., headache, dyspnea).[80]

5.5 Supportive Measures

Exercise rehabilitation programs have been shown to be helpful in reducing chest pain symptoms and improving pain tolerance in MVA patients,[81] and should therefore be recommended in those with refractory symptoms.

Psychologic interventions can also be helpful in the management of refractory MVA when psychologic disorders are present, both basically or as a consequence of angina status.[82] Various kinds of interventions have been assessed in small studies, including strategies for managing symptoms and for changing inappropriate beliefs and behavior, with improvement of psychologic morbidity and quality of life.[83] The effects of these measures seem to decrease over time.

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