**6. Cardiovascular disease associated with upper gastrointestinal symptom drug use**

In addition to cardiovascular drugs provoking upper gastrointestinal symptoms, a number of medications used to treat upper gastrointestinal symptoms have impacted cardiovascular drug function or have been associated with poor cardiovascular outcomes through both indirect and direct mechanisms.

#### **6.1. Drug interactions impeding cardiovascular drug function**

Proton pump inhibitors are frequently used to treat various gastrointestinal symptoms/ conditions including *H. pylori* infection. American College of Gastroenterology guidelines recommended strategies for the eradication of *H. pylori* infection include treatment with at least three drugs, and yield eradication rates of up to 90%. While the best *H. pylori* treatment regimen may vary depending on patient characteristics, guidelines recommended four different drug regimens including a proton pump inhibitor, clarithromycin, and amoxicillin, or metronidazole (clarithromycin-based triple therapy) for 14 days, a proton pump inhibitor or histamine-2-antagonist, bismuth, metronidazole, and tetracycline (bismuth quadruple therapy) for 10–14 days, or sequential therapy consisting of a proton pump inhibitor and amoxicillin for 5 days followed by a proton pump inhibitor, clarithromycin, and tinidazole for an additional 5 days (as an alternative to clarithromycin-based triple or bismuth quadruple therapy) [68].

Proton pump inhibitors competitively inhibit the cytochrome P450 2C19 isoenzyme (CYP2C19). Based on in vitro and in vivo data, omeprazole and esomeprazole are the most potent CYP2C19 inhibitors [69]. In vivo, omeprazole and esomeprazole induced 4 and 10 fold functional inhibition of CYP2C19 versus less than 1.5 fold inhibition with lansoprazole and pantoprazole [70]. Rabeprazole has in vitro data showing less inhibition of CYP2C19 than omeprazole and lansoprazole but no in vivo data is available [69].

Clopidogrel is a CYP2C19 substrate and needs to be activated by this isoenzyme. When given concurrently with proton pump inhibitors, there is a reduction in the produced active form of clopidogrel and greater platelet reactivity (less platelet inhibition) [71,72].

Whether this platelet reactivity effect impacts clinical events has been controversial. A 2009 population-based study among Ontario residents aged 66 years or older used prescription records to ascertain proton pump inhibitor use during clopidogrel therapy. The analysis suggested that proton pump inhibitor use may be associated with an increased risk of cardiovascular events [odds ratio for recurrent myocardial infarction within 90 days following hospital discharge, 1.27 (1.03 to 1.57)], however, no effect on the risk of death was observed [odds ratio of death within 90 days following hospital discharge 0.82 (0.57 to 1.18)] [73]. The 16,718 patient Clopidogrel Medco Outcomes Study was a cohort evaluation from an integrated medical and pharmacy claims database. Patients had a clopidogrel prescription filled within one month of a coronary stenting procedure (where dual aspirin and clopidogrel therapy is frequently employed). Patients who concomitantly received a proton pump inhibitor were in the active group while those without were in the control group in this observational non‐ randomized study. Those receiving a proton pump inhibitor had more cardiovascular events (myocardial infarction, unstable angina, repeat coronary procedure) than those without (25% vs. 18%, p<0.0001). Without randomization, however, it cannot be ascertained where it was the underlying patient population with gastrointestinal symptoms that had a higher risk or if the use of the proton pump inhibitor yielded the difference. When patients on each proton pump inhibitor were analyzed separately, there were no differences in the percent of patients with a cardiac event: omeprazole 25%, esomeprazole 25%, lansoprazole 24%, and pantoprazole 29%. Given the marked differences in CYP2C19 inhibition between omeprazole and esome‐ prazole versus lansoprazole and pantoprazole, qualitative differences between the groups would have been expected [74]. Two other smaller analyses also supported the greater risk of cardiac events with patients receiving concurrent proton pump inhibitors but again, whether

patients at risk for adverse cardiovascular outcomes. Studies have demonstrated that gastro‐ intestinal side effects decrease medication adherence [66], and this likely plays an important role in the poor adherence often seen across the spectrum cardiovascular medications [67].

**Table 8.** Cross-Comparison of Upper Gastrointestinal Symptoms Precipitated by Antithrombotics [46,47,56,65]

ASA=aspirin; COX=cyclooxygenase; NSAID=non-steroidal anti-inflammatory drug; NA=not available; PDE=phospho‐

**Agent Mechanism of Action UGIS Nausea**

++++ (indomethacin: >6%)

+++/++++ (drug dependent: 3-9%)

ASA Blockade of COX-1 ++++ (>6%) ++++ (>6%)

Cilostazol PDE III blockade ++++ (~6%) ++++ (~7%) Clopidogrel P2Y12 inhibition ++ (<2%) ++ (<2%) Prasugrel P2Y12 inhibition ++ (<2%) +++ (~5%) Ticagrelor P2Y12 inhibition ++ (~2%) +++ (~4%) Ticlopidine P2Y12 inhibition ++++ (~7%) ++++ (~7%)

Warfarin Vitamin K antagonist ++++ (6%) ++ (1.5%) Dabigatran Direct thrombin inhibition ++++ (11%) NA Rivaroxaban Factor Xa inhibition ++ (≤2%) ++ (2%) Apixaban Factor Xa inhibition NA +++ (3%)

Non-ASA NSAIDs Blockade of COX-1 +++ (ibuprofen, naproxen: 2-3%);

**6. Cardiovascular disease associated with upper gastrointestinal symptom**

In addition to cardiovascular drugs provoking upper gastrointestinal symptoms, a number of medications used to treat upper gastrointestinal symptoms have impacted cardiovascular drug function or have been associated with poor cardiovascular outcomes through both

Proton pump inhibitors are frequently used to treat various gastrointestinal symptoms/ conditions including *H. pylori* infection. American College of Gastroenterology guidelines recommended strategies for the eradication of *H. pylori* infection include treatment with at

**drug use**

*Antiplatelet agents*

156 Dyspepsia - Advances in Understanding and Management

*Anticoagulant agents*

indirect and direct mechanisms.

**6.1. Drug interactions impeding cardiovascular drug function**

++=minimal risk (≤2%); +++=moderate risk (3-5%); ++++=high risk (5-10%)

diesterase; UGIS=upper gastrointestinal symptoms

the additional risk is due to the underlying differences in the populations versus the use of the drug cannot be determined [75,76].

Cisapride is a promotility agent that enhances acetylcholine release at the myenteric plexus [56]. In March of 2000, the Food and Drug Administration was notified that the manufacturer would stop widespread manufacture of the drug due to elevated risk of QTc interval prolon‐ gation and the formation of the polymorphic ventricular tachycardia Torsade de Pointes. There are 341 reports of heart rhythm abnormalities, likely Torsade de Pointes, and 80 deaths with cisapride. It is still being made and distributed to individuals for whom other options have failed but is contraindicated with QTc interval prolonging agents such as Vaughn Williams Class Ia (quinidine, procainamide) or Class III (amiodarone, dronedarone, sotalol, dofetilide) antiarrhythmic agents, macrolide antibiotics (erythromycin, clarithromycin, troleandomycin), nefazodone, HIV protease inhibitors, and -azole antifungals. It is also contraindicated with potent CYP3A4 inhibitors and prone individuals [56, 80]. While not classically considered a gastrointestinal drug, erythromycin stimulates motilin receptors and can be an adjunctive promotility agent in diabetic gastroparesis. Erythromycin blocks the rapid component of the delayed rectifier potassium channel and prolongs the QTc interval and arrhythmogenic risk

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The 5HT3 antagonists (dolasetron, granisetron, etc) prolong the QTc interval and when used intravenously or in patients with other QTc interval prolonging drugs, hypokalemia or hypomagnesemia, or congenital long QT syndrome; can induce the polymorphic ventricular arrhythmia known as Torsade de Pointes [80]. Correcting electrolyte abnormalities before starting a 5HT3 antagonist is important in preventing Torsade de Pointes but is also sometimes

The 5HT3 antagonists (dolasetron, granisetron, ondansetron, etc) and the histamine 2 receptor antagonists (cimetidine, ranitidine) have been shown to rarely cause negative chronotropic (reduced sinoatrial nodal firing rate) and dromotropic (reduced rate of impulse passage through the atrioventricular node) effects when used in excessive doses or in intravenous forms [56, 80]. Patients who are prone to develop bradycardia or heart block, such as those with borderline low heart rates, elevated baseline PR intervals, or are receiving other negative chronotropic or dromotropic drugs (beta-blockers, nondihydropyridine calcium channel blockers, digoxin, Vaughn Williams Class Ic antiarrhythmic agents) are most at risk [56,80].

Metoclopramide is a complex dopaminergic agent with differing effects on blood pressure in different individuals. When used as a sole agent in normotensive, essential hypertensive, and type 2 diabetic subjects, there is no effect on systolic or diastolic blood pressure [81,82]. However, it can profoundly elevate blood pressure in patients with pheochromocytoma and in patients developing serotonin syndrome while taking metoclopramide with select serotonin reuptake inhibitors [83-86]. In addition, it has been shown to modestly attenuate the antihy‐ pertensive effects of bromocriptine and labetolol [87,88]. In this way, metoclopramide can induce hypertensive urgencies and emergencies in prone individuals and alternative agents

difficult given the emesis the drugs are being used to control [56].

**6.3. Bradycardia and atrioventricular blockade**

as well [80].

**6.4. Hypertension**

should be utilized when appropriate.

In the 13,608 patient TRITON-TIMI 38 Trial, a third of patients were on a concomitant proton pump inhibitor (41% pantoprazole, 37% omeprazole, 14% esomeprazole, 10% lansoprazole, 1% rabeprazole). In a nested cohort analysis from this trial, there was no difference between the proton pump inhibitor group and the control group for the composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke [77].

Given the profound effect of confounders, especially co-linear confounders, on the results of observational trials, these trials cannot prove causality, regardless of their results. Randomized and placebo controlled clinical trials eliminate many of these confounders and have much stronger internal validity. The only major randomized evaluation of the impact of proton pump inhibitors on cardiovascular events was the Clopidogrel and the Optimization of Gastrointes‐ tinal Events (COGENT) trial. Overall, 3761 patients starting dual antiplatelet therapy with aspirin and clopidogrel were randomized to receive omeprazole or placebo. No difference was found in the primary composite cardiovascular endpoint (p=0.98) but the rate of overt upper gastrointestinal bleeding was reduced with omeprazole therapy versus placebo [hazard ratio 0.13 (0.03 to 0.56)] [78]. The use of omeprazole which is the most potent CYP2C19 inhibitor was the best proton pump inhibitor choice to evaluate the balance of benefits to harms in this population [56, 69].

The COGENT trial and TRITON-TIMI 38 analysis results led the American College of Cardi‐ ology, American College of Gastroenterology, and American Heart Association to issue guidelines calling for the use of proton pump inhibitors when indicated for patients receiving antiplatelet therapy for cardiovascular disease [79]. However, the package insert recommends avoiding the use moderate to strong CYP2C19 inhibitors and to use alternative acid suppress‐ ing agents such as H2 antagonists or less potent CYP2C19 inhibiting proton pump inhibitors where possible [56].

Aside from proton pump inhibitors, the histamine-2 antagonist cimetidine is ubiquitous moderate CYP 1A2, 2C19, 2D6, and 3A4 inhibitor [56]. It raises the concentrations of all these cardiovascular medications increasing the chances for cardiovascular adverse effects. As such additional monitoring is suggested when added to amiodarone, beta-blockers (carvedilol, nebivolol), calcium channel clockers (verapamil, diltiazem, nifedipine), procainamide, propafenone, and ranolazine while selection of an alternative agent is specifically suggested when quinidine is being used. Other drugs in this class do not have the same potency of inhibition and are therapeutic alternatives [56].

#### **6.2. QTc prolongation and Torsade de Pointes**

Two classes of commonly used upper gastrointestinal drugs impact QTc prolongation and arrhythmogenesis. The QTc interval is a marker of ventricular depolarization and repolariza‐ tion time and if the QTc interval reaches 500ms or is elevated by 60ms over baseline values, the risk of the polymorphic ventricular arrhythmia Torsade de Pointes is elevated [80]. Torsade de Pointes can be a life threatening arrhythmia and requires prompt detection and treatment. Cisapride is a promotility agent that enhances acetylcholine release at the myenteric plexus [56]. In March of 2000, the Food and Drug Administration was notified that the manufacturer would stop widespread manufacture of the drug due to elevated risk of QTc interval prolon‐ gation and the formation of the polymorphic ventricular tachycardia Torsade de Pointes. There are 341 reports of heart rhythm abnormalities, likely Torsade de Pointes, and 80 deaths with cisapride. It is still being made and distributed to individuals for whom other options have failed but is contraindicated with QTc interval prolonging agents such as Vaughn Williams Class Ia (quinidine, procainamide) or Class III (amiodarone, dronedarone, sotalol, dofetilide) antiarrhythmic agents, macrolide antibiotics (erythromycin, clarithromycin, troleandomycin), nefazodone, HIV protease inhibitors, and -azole antifungals. It is also contraindicated with potent CYP3A4 inhibitors and prone individuals [56, 80]. While not classically considered a gastrointestinal drug, erythromycin stimulates motilin receptors and can be an adjunctive promotility agent in diabetic gastroparesis. Erythromycin blocks the rapid component of the delayed rectifier potassium channel and prolongs the QTc interval and arrhythmogenic risk as well [80].

The 5HT3 antagonists (dolasetron, granisetron, etc) prolong the QTc interval and when used intravenously or in patients with other QTc interval prolonging drugs, hypokalemia or hypomagnesemia, or congenital long QT syndrome; can induce the polymorphic ventricular arrhythmia known as Torsade de Pointes [80]. Correcting electrolyte abnormalities before starting a 5HT3 antagonist is important in preventing Torsade de Pointes but is also sometimes difficult given the emesis the drugs are being used to control [56].

#### **6.3. Bradycardia and atrioventricular blockade**

The 5HT3 antagonists (dolasetron, granisetron, ondansetron, etc) and the histamine 2 receptor antagonists (cimetidine, ranitidine) have been shown to rarely cause negative chronotropic (reduced sinoatrial nodal firing rate) and dromotropic (reduced rate of impulse passage through the atrioventricular node) effects when used in excessive doses or in intravenous forms [56, 80]. Patients who are prone to develop bradycardia or heart block, such as those with borderline low heart rates, elevated baseline PR intervals, or are receiving other negative chronotropic or dromotropic drugs (beta-blockers, nondihydropyridine calcium channel blockers, digoxin, Vaughn Williams Class Ic antiarrhythmic agents) are most at risk [56,80].

#### **6.4. Hypertension**

the additional risk is due to the underlying differences in the populations versus the use of the

In the 13,608 patient TRITON-TIMI 38 Trial, a third of patients were on a concomitant proton pump inhibitor (41% pantoprazole, 37% omeprazole, 14% esomeprazole, 10% lansoprazole, 1% rabeprazole). In a nested cohort analysis from this trial, there was no difference between the proton pump inhibitor group and the control group for the composite endpoint of

Given the profound effect of confounders, especially co-linear confounders, on the results of observational trials, these trials cannot prove causality, regardless of their results. Randomized and placebo controlled clinical trials eliminate many of these confounders and have much stronger internal validity. The only major randomized evaluation of the impact of proton pump inhibitors on cardiovascular events was the Clopidogrel and the Optimization of Gastrointes‐ tinal Events (COGENT) trial. Overall, 3761 patients starting dual antiplatelet therapy with aspirin and clopidogrel were randomized to receive omeprazole or placebo. No difference was found in the primary composite cardiovascular endpoint (p=0.98) but the rate of overt upper gastrointestinal bleeding was reduced with omeprazole therapy versus placebo [hazard ratio 0.13 (0.03 to 0.56)] [78]. The use of omeprazole which is the most potent CYP2C19 inhibitor was the best proton pump inhibitor choice to evaluate the balance of benefits to harms in this

The COGENT trial and TRITON-TIMI 38 analysis results led the American College of Cardi‐ ology, American College of Gastroenterology, and American Heart Association to issue guidelines calling for the use of proton pump inhibitors when indicated for patients receiving antiplatelet therapy for cardiovascular disease [79]. However, the package insert recommends avoiding the use moderate to strong CYP2C19 inhibitors and to use alternative acid suppress‐ ing agents such as H2 antagonists or less potent CYP2C19 inhibiting proton pump inhibitors

Aside from proton pump inhibitors, the histamine-2 antagonist cimetidine is ubiquitous moderate CYP 1A2, 2C19, 2D6, and 3A4 inhibitor [56]. It raises the concentrations of all these cardiovascular medications increasing the chances for cardiovascular adverse effects. As such additional monitoring is suggested when added to amiodarone, beta-blockers (carvedilol, nebivolol), calcium channel clockers (verapamil, diltiazem, nifedipine), procainamide, propafenone, and ranolazine while selection of an alternative agent is specifically suggested when quinidine is being used. Other drugs in this class do not have the same potency of

Two classes of commonly used upper gastrointestinal drugs impact QTc prolongation and arrhythmogenesis. The QTc interval is a marker of ventricular depolarization and repolariza‐ tion time and if the QTc interval reaches 500ms or is elevated by 60ms over baseline values, the risk of the polymorphic ventricular arrhythmia Torsade de Pointes is elevated [80]. Torsade de Pointes can be a life threatening arrhythmia and requires prompt detection and treatment.

cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke [77].

drug cannot be determined [75,76].

158 Dyspepsia - Advances in Understanding and Management

population [56, 69].

where possible [56].

inhibition and are therapeutic alternatives [56].

**6.2. QTc prolongation and Torsade de Pointes**

Metoclopramide is a complex dopaminergic agent with differing effects on blood pressure in different individuals. When used as a sole agent in normotensive, essential hypertensive, and type 2 diabetic subjects, there is no effect on systolic or diastolic blood pressure [81,82]. However, it can profoundly elevate blood pressure in patients with pheochromocytoma and in patients developing serotonin syndrome while taking metoclopramide with select serotonin reuptake inhibitors [83-86]. In addition, it has been shown to modestly attenuate the antihy‐ pertensive effects of bromocriptine and labetolol [87,88]. In this way, metoclopramide can induce hypertensive urgencies and emergencies in prone individuals and alternative agents should be utilized when appropriate.

The consequences of these drug-disease interactions can be dire, with significant impact on mortality and morbidities. As many of these interactions are unknown until a large population has been using the offending medications, health care providers must remain vigilant in identifying potential new problems.

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