Atrial fibrillation (AF) is the most common arrhythmia in the world. Risk factor modification, anticoagulation, rhythm control, and rate control are the four pillars of its management. American College of Cardiology/American Heart Association (ACC/AHA) guidelines on management of AF were updated recently.

A synthetic form of the protein apoaequorin is the active ingredient in the over-the-counter dietary supplement Prevagen (Quincy Bioscience), which is heavily marketed to improve memory.

Opioids delay gastric emptying and the absorption of many oral drugs, including the P2Y₁₂ inhibitors clopidogrel (Plavix, and generics), prasugrel (Effient, and generics), and ticagrelor (Brilinta), which are commonly used for initial treatment of acute coronary syndrome (ACS). An article in our February 25, 2019 issue reviewed studies showing that coadministration of opioids delayed and decreased absorption of oral P2Y₁₂ inhibitors and increased platelet reactivity. Recently published clinical outcomes data may add to these concerns.

The FDA has required manufacturers of the oral P2Y₁₂ platelet inhibitors clopidogrel (Plavix, and generics), prasugrel (Effient, and generics), and ticagrelor (Brilinta) to warn in the product labels that the absorption of these drugs may be delayed or reduced when taken with an opioid agonist.

The antiplatelet drug clopidogrel (Plavix, and others) reduces major cardiovascular events, but can cause bleeding. Proton pump inhibitors (PPIs) are often used with clopidogrel to prevent gastrointestinal bleeding, however, some evidence suggests that PPIs may interfere with the activation of clopidogrel and diminish its antiplatelet effect. FDA-approved labeling recommends avoiding concurrent use of the PPIs omeprazole and esomeprazole with clopidogrel.

The FDA has approved cangrelor (Kengreal – The Medicines Company), an IV P2Y12 platelet inhibitor, as an adjunct to percutaneous coronary intervention (PCI) in patients who have not been pretreated with a P2Y12 inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.

Recent guidelines from the American Heart Association and American Stroke Association reviewed antithrombotic therapy options for secondary prevention of stroke in patients who have had a stroke or transient ischemic attack (TIA).

Antiplatelet drugs are the drugs of choice for prevention and treatment of arterial thrombosis. Anticoagulants are the drugs of choice for prevention and treatment of venous thromboembolism and for prevention of cardioembolic events in patients with atrial fibrillation.

The FDA has approved vorapaxar (Zontivity – Merck), an oral protease-activated receptor-1 (PAR-1) antagonist, for use with aspirin and/or clopidogrel to reduce the risk of thrombotic cardiovascular events in patients with peripheral arterial disease or a history of myocardial infarction (MI). It is the first PAR-1 antagonist to be approved by the FDA.

H2-RECEPTOR ANTAGONISTS (H2RAs) — Currently available H2RAs are listed in Table 1. These drugs inhibit the action of histamine at the H2-receptor of the gastric parietal cell, decreasing basal acid secretion and, to a lesser degree, food-stimulated acid secretion. All H2RAs are about equally effective for treatment of PUD and GERD. H2RAs are faster acting than PPIs in relieving symptoms of dyspepsia or GERD, but they are not as effective as PPIs in relieving symptoms or in healing erosive esophagitis. Repeated administration of H2RAs leads to pharmacologic tolerance and has been associated with the development of new dyspeptic symptoms. Rebound acid hypersecretion can occur after stopping H2RAs.

The use of intracoronary stents in angioplasty procedures has improved both short- and long-term success rates. In recent years, drug-eluting stents (DESs) have largely replaced bare-metal stents (BMSs).

The standard antithrombotic therapy for treatment of patients with acute coronary syndrome (ACS) is dual antiplatelet therapy with aspirin and clopidogrel (Plavix) or another thienopyridine, plus a parenteral anticoagulant while the patient is hospitalized, followed by antiplatelet therapy alone after discharge. The addition of the oral anticoagulant warfarin (Coumadin, and others) to dual antiplatelet therapy is generally not recommended for this indication because of fluctuations in its anticoagulant effect and the risk of bleeding. A recently published trial found that addition of a low dose of the oral anticoagulant rivaroxaban (Xarelto) to antiplatelet therapy after discharge reduced the risk of major cardiovascular events without increasing the incidence of fatal bleeding.

Arterial thrombi are composed mainly of platelet aggregates held together by small amounts of fibrin. Antiplatelet drugs are the drugs of choice for prevention and treatment of arterial thrombosis, but anticoagulants are also effective, and their effects can add to those of antiplatelet drugs. Venous thrombi are composed mainly of fibrin and trapped red blood cells, with relatively few platelets. Anticoagulants are the agents of choice for prevention and treatment of venous thromboembolism and for prevention of cardioembolic events in patients with atrial fibrillation.

The FDA has approved ticagrelor (Brilinta – AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months.

Peptic ulcer disease (PUD) is usually caused by nonsteroidal anti-inflammatory drugs (NSAIDs) or by infection with Helicobacter pylori. Gastroesophageal reflux disease (GERD) can be caused by transient lower esophageal sphincter relaxation, reduced lower esophageal sphincter tone, hiatal hernia, delayed gastric emptying or hormonal changes due to pregnancy. Acid suppressive therapy is the cornerstone of management for both PUD and GERD.

Use of a proton pump inhibitor (PPI) to protect against gastrointestinal (GI) bleeding in patients taking the antiplatelet agent clopidogrel (Plavix) may interfere with the activation of clopidogrel and diminish its antiplatelet effect, increasing the risk of cardiovascular events.1 A randomized, placebo-controlled trial (COGENT) has found that use of the PPI omeprazole in patients taking clopidogrel in addition to aspirin decreased the incidence of GI bleeding without increasing the risk of a cardiovascular event, but the number of cardiovascular events was small and the formulation of omeprazole was atypical.2 The FDA in the same issue of the same journal cautioned against concluding from the results of COGENT that concurrent use of clopidogrel and omeprazole is safe.3

To some extent, all PPIs reduce the enzymatic activity of CYP2C19, which is thought to be mainly responsible for the bioactivation of clopidogrel. Omeprazole is a strong inhibitor of CYP2C19; pantoprazole (Protonix, and others) appears to have less effect on CYP2C19 and not to attenuate the antiplatelet effect of clopidogrel.4-6 Medical Letter consultants believe that patients at risk for upper GI bleeding who take clopidogrel should also take a PPI, but not omeprazole. Until more data become available on other PPIs, pantoprazole would be a reasonable choice.

1. PPI interactions with clopidogrel revisited. Med Lett Drugs Ther 2009; 51:13.

2. DL Bhatt et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363:1909.

3. MR Southworth and R Temple. Interaction of clopidogrel and omeprazole. N Engl J Med 2010; 363:1977.

4. DJ Angiolillo et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 2010; Sept 15 epub.

5. T Cuisset et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose: the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009; 54:1149.

6. H Neubaurer et al. Pantoprazole does not influence the antiplatelet effect of clopidogrel – a whole blood aggregometry study after coronary stenting. J Cardiovasc Pharmacol 2010; 56:91.

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The FDA has required the manufacturer of Plavix, an antiplatelet drug used in addition to aspirin to prevent cardiovascular events in high-risk patients,1 to add a boxed warning to the package insert about the risk of a poor response to the drug in patients with genetic polymorphisms of the cytochrome P450 enzyme CYP2C19. Clopidogrel is a prodrug and CYP2C19 is mainly responsible for its bioactivation. The Medical Letter reported last year that several studies have found higher rates of cardiovascular events, including stent thrombosis, in patients with these polymorphisms taking clopidogrel.2

At least one genetic polymorphism leading to poor metabolism of clopidogrel has been reported to occur in 15% of Caucasians, 17% of African Americans and 30% of Asians.3 Since many patients take clopidogrel to protect against life-threatening events, and some continue to do so for extended periods of time, it might be worthwhile to test for these polymorphisms. Such tests, requiring small amounts of blood or saliva, are commercially available from clinical laboratories. More directly, patients who are taking clopidogrel could have platelet aggregation assays to determine whether the drug is being activated.

However, the best course of action for patients who prove to be poor metabolizers of clopidogrel is not clear. They could be treated with higher doses of clopidogrel, but the doses that would be safe and effective in such patients have not been established. Alternatively, they could be treated with prasugrel (Effient), a similar antiplatelet drug that does not require CYP2C19 for activation, instead of clopidogrel, but prasugrel has a greater effect on platelets and may cause more bleeding.4

1. Antiplatelet and anticoagulant drugs. Treat Guidel Med Lett 2008; 6:29.
2. PPI interactions with clopidogrel revisited. Med Lett Drugs Ther 2009; 51:13.
3. Z Desta et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41:913.
4. Prasugrel (Effient) vs. clopidogrel (Plavix). Med Lett Drugs Ther 2009; 51:69.

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Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are common causes of peptic ulcer disease. Patients infected with Helicobacter pylori who take aspirin or another NSAID have an especially high risk. Drugs that have been tried for prevention of ulcers in patients taking NSAIDs including H₂-receptor antagonists, proton pump inhibitors (PPIs), aluminum- or magnesium-containing antacids, the prostaglandin misoprostol (Cytotec, and others), and antibiotics to eradicate H. pylori.

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The FDA has approved prasugrel (Effient - Lilly/Daiichi Sankyo), an oral antiplatelet drug, for use with aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndromes (ACS) being managed with percutaneous coronary intervention (PCI). It will compete with clopidogrel (Plavix) for such use.

Atrial fibrillation increases the risk of stroke by a factor of 5. A randomized controlled trial (ACTIVE W) in 6706 patients with atrial fibrillation and one or more additional risk factors (≥75 years old; hypertension; previous stroke, transient ischemic attack or non- CNS embolus; left ventricular ejection fraction <45%; peripheral vascular disease; or 55-74 years old plus diabetes or coronary artery disease) found that a vitamin K antagonist such as warfarin (Coumadin, and others) was superior to clopidogrel (Plavix) plus aspirin in preventing vascular events, especially ischemic stroke.1

Now another study (ACTIVE A) from the same group of investigators has compared addition of clopidogrel to aspirin with aspirin alone in 7554 patients with atrial fibrillation and one or more additional risk factors for stroke. All of these patients were considered “unsuitable” for treatment with a vitamin K antagonist. Vascular events, primarily stroke, occurred significantly more often with aspirin alone. Major bleeding occurred significantly more often with aspirin plus clopidogrel.2

Oral anticoagulation with a vitamin K antagonist such as warfarin continues to be the treatment of choice for patients with atrial fibrillation and one or more additional risk factors for stroke.3-5 In patients who cannot or will not take a vitamin K antagonist, clopidogrel plus aspirin appears to be more effective in preventing stroke than aspirin alone.

1. ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903.

2. ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066.

3. Antiplatelet and anticoagulant drugs. Treat Guidel Med Lett 2008; 6:29.

4. DE Singer et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6 suppl): 546S.

5. AS Go. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N Engl J Med 2009; 360:2127.

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The FDA has approved the proton-pump inhibitor (PPI) dexlansoprazole (Kapidex - Takeda), a delayed release formulation of the R-enantiomer of lansoprazole (Prevacid - Takeda), for treating and maintaining healing of erosive esophagitis and for treatment of heartburn associated with non-erosive gastroesophageal reflux disease (GERD).

Current guidelines recommend use of a proton pump inhibitor (PPI) to decrease the risk of gastrointestinal bleeding in patients taking clopidogrel (Plavix) with aspirin. A recent issue of The Medical Letter considered whether omeprazole (Prilosec, and others) or other PPIs could interfere with the antiplatelet effect of clopidogrel. The conclusion was that patients taking both drugs should probably continue to do so until more data became available. Several new publications require reconsideration of that recommendation.

Clopidogrel (Plavix), which prevents arterial thrombosis by inhibiting platelet activation, is commonly prescribed (usually with aspirin) for months after acute coronary syndromes and stent implantation. It may also, however, increase the risk of bleeding. Therefore, a proton pump inhibitor (PPI) such as omeprazole (Prilosec, and others) is often given concurrently to decrease the risk of gastrointestinal (GI) bleeding. Some reports have suggested that omeprazole may interfere with the antiplatelet effect of clopidogrel.

The antiplatelet agents aspirin and clopidogrel (Plavix, and others) are used in most patients undergoing percutaneous coronary intervention (PCI) to prevent stent thrombosis and to reduce the occurrence of peri-, post-procedural and late cardiovascular events. Despite a large number of randomized trials of these agents in such patients, the optimal dosage and duration of treatment with these drugs, and whether other drugs should be added, is unclear.

Arterial and venous thrombosis are major causes of morbidity and mortality. Arterial thrombi consist of platelet aggregates held together by small amounts of fibrin. Antiplatelet drugs are the drugs of choice for prevention and treatment of arterial thrombosis, but anticoagulants are also effective, and their effects can add to those of antiplatelet drugs. Venous thrombi are composed mainly of fibrin and trapped red blood cells, with relatively few platelets. Anticoagulants are the agents of choice for prevention and treatment of venous thromboembolism and for prevention of cardioembolic events in patients with atrial fibrillation.

Clopidogrel (Plavix - Sanofi-Aventis and Bristol-Myers Squibb), an oral thienopyridine that inhibits platelet aggregation, is now being advertised directly to the public on television. Clopidogrel is approved by the FDA for secondary prevention of myocardial infarction (MI), stroke and other vascular events and for use in patients with acute coronary syndrome (unstable angina or non-ST-elevation MI), including those undergoing angioplasty. It is used off-label for patients with ST-elevation acute MI

Percutaneous coronary intervention (PCI), such as balloon angioplasty or stent placement, predisposes to subsequent thrombosis. The current pharmacologic approach to prevention of this problem combines an anticoagulant with one or more antiplatelet drugs.

Management of intermittent claudication, the most common symptom of peripheral arterial disease (PAD), involves both risk factor modification and symptomatic treatment (WR Hiatt, N Engl J Med 2001; 344:1608; RM Schainfeld, J Am Board Fam Pract 2001; 14:443).

Aggrenox, a fixed-dose oral combination of aspirin and extended-release dipyridamole, is now being advertised for secondary prevention of a transient ischemic attack (TIA) or ischemic stroke.

Cilostazol, a phosphodiesterase III inhibitor that has been used in Japan since 1988, has been approved by the FDA for treatment on intermittent claudication due to occlusive peripheral arterial disease.

Clopidogrel bisulfate (Plavix - Bristol-Myers Squibb/Sanofi), a new thienopyridine antiplatelet agent similar to ticlopidine (Ticlid - Medical Letter, 34:65, 1992), has been approved by the US Food and Drug Administration (FDA) for secondary prevention of myocardial infarction, stroke and other vascular events.