Mghr on for 1214 hours off for 101 hours

Common adverse effects of nitrates include postural hypotension, flushing, and headache secondary to venodilation. Headache often resolves with continued therapy and may be treated with acetaminophen. Hypotension is generally of no serious consequence. However, in patients with hypertrophic obstructive cardiomyopathy or severe aortic valve stenosis, nitroglycerin may cause serious hypotension and syn-

cope. Therefore, long-acting nitrates are relatively contraindicated in these conditions. Because life-threatening hypotension may occur with concomitant use of nitrates and phosphodiesterase type 5 inhibitors, nitrates should not be used within 24 hours of taking sildenafil or vardenafil or within 48 hours of taking tadalafil. Skin erythema and inflammation may occur with transdermal nitroglycerin administration and may be minimized by rotating the application site.


Ranolazine is an anti-ischemic agent that exerts its effects by inhibiting the late inward sodium current during the plateau phase of the cardiac action potential. Under ischemic conditions, excess sodium may enter the myocardial cell during systole. The resultant intracellular sodium overload leads to intracellular calcium accumulation (calcium overload) though a sodium/calcium exchange mechanism. Calcium overload results in increases in left ventricular wall tension and myocardial oxygen consumption. By reducing intracellular sodium concentrations, ranolazine decreases calcium overload, left ventricular wall tension, and myocardial oxygen consumption.

In clinical trials, ranolazine at a dose of 750 to 1,000 mg twice daily improved angina and increased exercise capacity when added to other antianginal therapy.35,36 Ranolazine has minimal effects on heart rate or blood pressure; however, it has the potential to prolong the QT interval and increase the risk for the life-threatening arrhythmia, torsades de pointes. Therefore, ranolazine should be reserved for patients with angina that is refractory to traditional antianginal medications. Contraindications to ranolazine are shown in Table 7-10. Common adverse effects with ranolazine include dizziness, headache, constipation, and nausea. Syncope may occur infrequently. Ranolazine is a substrate for CYP3A4 and both an inhibitor and substrate of p-gly-coprotein. Concomitant use of ranolazine with moderate to potent CYP3A4 inhibitors, including verapamil and diltiazem, is contraindicated. Ranolazine should be used cautiously with p-glycoprotein inhibitors (e.g., cyclosporine) and substrates (e.g., digox-in).

Pharmacotherapy With No Benefit or Potentially Harmful Effects Hormone Replacement Therapy

Hormone replacement therapy (HRT) has favorable effects on lipoprotein cholesterol concentrations. Data from several observational studies suggested that HRT might reduce the risk of cardiovascular events in women with IHD. However, subsequent randomized, controlled, clinical trials failed to demonstrate a reduction in the risk for

37 38

IHD or cardiovascular events with HRT in postmenopausal women. ' In fact, HRT appeared to be harmful in this patient population, increasing the risk of thromboem-bolic events and breast cancer. Current guidelines recommend against the use of HRT to reduce cardiovascular risk.1 Furthermore, the clinician should consider discontinuing HRT therapy in women who suffer an acute coronary event while receiving such therapy.


Oxidization of LDL-cholesterol is believed to play a significant role in the atherosclerotic process. The antioxidant vitamins, vitamin E, vitamin C, and P-carotene, protect LDL cholesterol from oxidation. Evidence from observational and animal studies suggested that increased intake of antioxidant vitamins might inhibit the formation of

atherosclerotic lesions and decrease the risk for cardiovascular events. However, a meta-analysis of several large, randomized, prospective studies found no beneficial effect of vitamin E or P-carotene on cardiovascular outcomes in patients with IHD or IHD risk factors.40,41 Similarly disappointing results were demonstrated with vitamin C supplementation. Based on this evidence, current guidelines do not recommend supplementation with vitamin E or other antioxidants for the sole purpose of preventing cardiovascular events.

Table 7-10 Contraindications and Precautions With Ranolazine



Pre existing QT prolongation

History of torsades de pointes

Uncorrected hypokalemia

I lepatic impairment

Treatment with other QT prolonging drugs

Treatment with moderate to potent CYP3A4 inhibitors, including ketaconazole. verapamil diltiazem, and St. John's wort

Treatment with C Y Pi A4 inducers, including rifampin, phénobarbital, Phenytoin, and carbamezpiner may significantly decrease the efficacy of ra no lapine (by 95% with rifampil)

Treatment with a p-glycoprotein inhibitor may increase ranolazine absorption

Ranolazine may increase bioavailability of p-glycoprotein substrates (increases digoxin plasma concentrations by l.^-fold)

Ranolazine may cause syncope; use Cili.ll on WI '■"- ■:!- ■ ■ - I ■ : I ■■:■.■. Lil'iC machinery

Ranolazine may cause reduced metabolism of CYP2D6 substrates

Folic Acid

Elevated homocysteine concentrations have been associated with an increased risk for cardiovascular disease in both epidemiologic and clinical studies.43 Several studies have evaluated the benefit of lowering homocysteine levels with folic acid, vitamin B6 and/or vitamin B12 supplementation. Despite lowering homocysteine levels, neither folic acid nor other vitamin B supplementation has been shown to reduce cardiovascular events in randomized controlled clinical trials.44,45 Based on available evidence, the use of folate or vitamin B supplementation for the purpose of preventing cardiovascular events in patients with pre-existing IHD or at risk for IHD is not recommended.

Herbal Supplements

Herbal products are widely used for their purported cardiovascular benefits; examples of such products include danshen, dong quai, feverfew, garlic, hawthorn, and hellebore. However, strong evidence supporting their benefits in cardiovascular disease is generally lacking. While small randomized controlled trials have shown benefits with some herbal supplements, the potential for drug interactions and the lack of product standardization limits the products' usefulness in clinical practice. Safety with herbal supplements in patients with IHD is a major concern. Unlike prescription and OTC medicines, the FDA does not require manufacturers of herbal products to submit proof of safety prior to product marketing. Numerous case reports of adverse cardiovascular events, including stroke, MI, and lethal cardiac arrhythmias with ephedra-based products (e.g., Ma huang) led the FDA to ban ephedra-containing products in 2004. However, other herbal supplements with potentially serious adverse cardiovascular effects remain easily accessible to the consumer (e.g., bitter orange). Some herbal supplements may interact with antiplatelet and antithrombotic therapy and increase bleeding risk (e.g., ginkgo biloba). Others may reduce the effectiveness of antianginal medications. Thus, it is important to assess the use of herbal products in patients with IHD and to counsel patients about the potential for drug interactions and adverse events with herbal therapies.

Cyclooxygenase-2 (COX-2) Inhibitors and NSAIDs

Data suggest that COX-2 inhibitors and nonselective NSAIDs may increase the risk for MI and stroke.46,47 The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The COX-2 inhibitors rofecoxib and valdecoxib were withdrawn from the market in recent years because of safety concerns. The FDA requested the manufacturers of other COX-2 and nonselective NSAIDs (prescription and OTC) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.46 Patients with cardiovascular disease should consult a clinician before using OTC NSAIDs.


Variant Angina

Vasospasm as the sole etiology of angina (Prinzmetal or variant angina) is relatively uncommon. As a result, treatment options are not well studied. Nevertheless, based on the pharmacology of available drugs, several recommendations can be made. First, P-blockers should be avoided in patients with variant angina because of their potential to worsen vasospasm due to unopposed a-adrenergic receptor stimulation. In contrast, both CCBs and nitrates are effective in relieving vasospasm and are preferred in the management of variant angina. Nitrates have several limitations outlined above, most notably the need for an 8-to 12-hour nitrate-free interval. Therefore, the role of monotherapy with long-acting nitrates as prophylaxis for anginal attacks due to vasospasm is limited. However, immediate-release nitroglycerin is effective at terminating acute anginal attacks due to vasospasm. Therefore, all patients diagnosed with variant angina should be prescribed immediate-release nitroglycerin. CCBs are effective for monotherapy of variant angina. Since short-acting CCBs have been associated with increased risk of adverse cardiac events, they should be avoided.34 Long-acting nitrates maybe added to CCB therapy if needed.

Elderly Patients With IHD

Elderly patients are more likely than younger patients to have other comorbidities that may influence drug selection for the treatment of angina. As a result, polypharmacy is more common in elderly patients, increasing the risk of drug-drug interactions, and perhaps decreasing medication adherence. Additionally, elderly patients are often more susceptible to adverse effects of antianginal therapies, particularly the negative chronotropic and inotropic effects of P-blockers and CCBs. Therefore, drugs should be initiated in low doses with close monitoring of elderly patients with IHD.

Patient Encounter, Part 3: Creating a Care Plan

Based on the information presented, create a specific plan for the management of RJ's ischemic heart disease. Your plan should include:

(1) the goals of therapy;

(2) specific nonpharmacologic and pharmacologic interventions to address these goals; and

(3) a plan for follow-up to assess drug tolerance and whether the therapeutic goals have been achieved.

Acute Coronary Syndrome

The management of ACS is discussed in further detail in the chapter on acute coronary syndromes. It is important to educate patients with IHD on the signs of ACS and what to do if they appear. Importantly, patients should be instructed to seek emergent care if symptoms of angina last longer than 20 to 30 minutes, do not improve after 5 minutes of using sublingual nitroglycerin, or worsen after 5 minutes of using sublingual nitroglycerin. In patients with a history of ACS, it is crucial to select appropriate phar-macotherapy to prevent recurrent ACS and death. Appropriate pharmacotherapy for patients with a history of ACS includes aspirin (perhaps in combination with clopido-grel), ACE inhibitors or ARBs, P-blockers, and statins. In addition, determining appropriate goals and instituting appropriate therapy to meet the goals for cardiovascular risk factors (e.g., dyslipidemia, hypertension, and diabetes) is critical.


Assessing for Drug Effectiveness and Safety

Monitor symptoms of angina at baseline and at each clinic visit for patients with IHD to assess the effectiveness of antianginal therapy. In particular, assess the frequency and intensity of anginal symptoms. Determining the frequency of sublingual nitroglycerin use is helpful in making this assessment. If angina is occurring with increasing frequency or intensity, adjust antianginal therapy and refer the patient for additional diagnostic testing (e.g., coronary angiography) and possibly for coronary interventions (e.g., PCI or CABG surgery).

• Assess the patient for IHD-related complications, such as heart failure. The presence of new comorbidities may indicate worsening IHD requiring additional workup or pharmacologic therapy.

• Routinely monitor hemodynamic parameters to assess drug tolerance. Assess blood pressure at baseline, after drug initiation and dose titration, then periodically thereafter in patients treated with ft-blockers, CCBs, nitrates, ACE inhibitors, and/or ARBs.

• Blood pressure reduction may be particularly pronounced after initiation and dose titration of P-blockers that also possess a-blocking effects (e.g., labetalol and carvedilol).

• Because of the potential for postural hypotension, warn patients that dizziness, pre-syncope, and even syncope may result from abrupt changes in body position during initiation or up-titration of drugs with a-blocking effects.

Closely monitor heart rate in patients treated with drugs that have negative chronotropic effects (e.g., ft-blockers, verapamil, or diltiazem) or drugs that may cause reflex tachycardia (e.g., nitrates or dihydropyridine CCBs).

• Treatment with P-blockers, verapamil, or diltiazem can usually be continued in patients with asymptomatic bradycardia. However, reduce or discontinue treatment with these agents in patients who develop symptomatic bradycardia or serious conduction abnormalities.

• Regularly assess control of existing risk factors and the presence of new risk factors for IHD. Routine screening for the presence of metabolic syndrome will help in assessing the control of known major risk factors and identifying new risk factors. If new risk factors are identified and/or the presence of metabolic syndrome is detected, modify the pharmacotherapy regimen, as discussed previously, to control these risk factors and lower the risk of IHD and IHD-related adverse events.

In patients treated with ACE inhibitors and/or ARBs, routinely monitor renal function and potassium levels at baseline, after drug initiation and dose titration, then periodically thereafter. This is particularly important when using these therapies in patients with pre-existing renal impairment or diabetes as they may be more susceptible to these adverse events.

Duration of Therapy

• Drugs that modify platelet activity, lipoprotein concentrations, and neurohormonal systems reduce the risk for coronary events and death. However, these therapies do not cure IHD.

• Treatment with antiplatelet (aspirin or clopidogrel), lipid-lowering, and neurohormonal-modifying therapy for IHD is generally lifelong. Similarly, antianginal therapy with a P-blocker, CCB, and/or nitrate is usually long term.

• A patient with severe symptoms managed with combination antianginal drugs who undergoes successful coronary revascularization maybe able to reduce antiangin-

al therapy. However, treatment with at least one agent that improves the balance between myocardial oxygen demand and supply is usually warranted.

Patient Care and Monitoring

1. Assess the patient's symptoms to determine whether the patient should be evaluated by a physician.

• Determine the quality, location, and duration of pain.

• Determine factors that provoke and relieve pain.

• Are symptoms characteristic of angina?

2. Identify risk factors for IHD.

• Are there any modifiable risk factors?

3. Obtain a thorough history of prescription drug, nonprescription drug, and herbal product use.

• Is the patient taking any medications/supplements that may exacerbate angina or interact with antianginal drug therapy?

4. Educate the patient on lifestyle modifications to control risk factors for IHD.

5. Is the patient taking appropriate drug therapy to prevent ACS and death? If not, why?

6. Is the patient taking appropriate antianginal therapy? If not, why?

7. Develop a plan to assess effectiveness of anti-ischemic therapy after 1 to 2 weeks.

8. Evaluate the patient to assess for adverse drug reactions, drug intolerance, and drug interactions.

9. Stress the importance of adherence with the therapeutic regimen, including lifestyle modifications.

10. Provide patient education regarding disease state, lifestyle modifications, and drug therapy:

• What are the consequences of untreated IHD?

• What lifestyle modifications should the patient follow?

• When should the patient take his or her medications?

• What potential adverse drug effects may occur?

• Teach the patient how to monitor heart rate and blood pressure to assess tolerance to antianginal therapy.

• Which drugs may interact with therapy or worsen IHD?

• What should the patient do when chest pain or its equivalent occurs?

• When should the patient seek emergent care?

Abbreviations Introduced in This Chapter

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