Proton Pump Inhibitors and Cardiovascular Risk: MI Harmless or Hazardous?

Ashley Rogers, PharmD PGY-2 Ambulatory Care Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center The University of Texas Health Science Center at San Antonio

September 18, 2015

Objectives:

1. Review indications, adverse effects and pharmacokinetic characteristics of proton pumpinhibitors.

2. Discuss the mechanisms for cardiovascular risk due to proton pump inhibitors.3. Evaluate available literature investigating cardiovascular risk in patients taking proton

pump inhibitors.4. Formulate a recommendation concerning risk versus benefit of proton pump inhibitors and

cardiovascular risk.

1 | R o g e r s

Proton Pump Inhibitors

I. Epidemiology A. Proton Pump Inhibitors (PPI) are the third highest selling drug class1

i. Over 21 million people with at least one prescription PPI in 20092

ii. Total 113.4 million prescriptions for $13.9 billion in sales1

B. Veteran Affairs observational study3 i. Initial prescription for 90 day supply: 66%

ii. No documentation of symptoms at initiation: 33%C. Estimated that 53-69% of PPI prescriptions are for inappropriate indications4 D. Over-the-counter (OTC) use as of 2003

II. Agents5-11

A. Availability i. Prescription

ii. OTCiii. Various formulations

a. Capsuleb. Tabletc. Oral packets for suspensiond. Intravenous

Table 1. Available Oral PPI5-11

PPI Prescription OTC

Omeprazole (Prilosec©) Capsule: 20mg, 40mg Capsule: 20mg

Omeprazole-sodium bicarbonate (Zegerid©)

Tablet & Oral Packet: 20mg/1100mg, 40mg/1100mg

Tablet: 20mg/1100mg

Esomeprazole (Nexium©) Capsule: 20mg, 40mg Oral Packet: 20mg, 40mg

Capsule: 22.3mg

Pantoprazole (Protonix©) Tablet: 20mg, 40mg Oral Packet: 40mg

Not available

Lansoprazole (Prevacid©) Capsule: 15mg, 30mg ODT: 15mg, 30mg

Capsule: 15mg

Rabeprazole (Aciphex©) Tablet: 20mg Capsule: 5mg, 10mg

Not available

Dexlansoprazole (Dexilant©) Capsule: 30mg, 60mg Not available

B. Mechanism of Action i. Suppresses gastric acid secretion by specific inhibition of the hydrogen-

potassium adenosine triphosphatase enzyme system found at the secretorysurface of parietal cells

ii. Inhibits final transport of hydrogen ions into the gastric lumeniii. Dose-relatediv. Inhibits both basal and stimulated parietal cells

2 | R o g e r s

Figure 1. PPI Mechanism of Action12

C. Pharmacokinetics5-11 i. Absorption

a. Tmax 30 minutes to 3.5 hoursb. Bioavailability varies per agent (30%-90%)c. Food decreases rate of absorption and exposure

ii. Distributiona. Volume varies per agent (0.3 to 24 L/kg)b. Heavily protein bound >90%

iii. Extensive hepatic metabolism

Table 2. Metabolism Pathway5-11

Proton Pump Inhibitor Metabolism Inhibition

Omeprazole Primarily: CYP2C19 Lesser extent: CYP3A4

2C19 & 2C9

Esomeprazole 2C19

Pantoprazole

CYP2C19 and CYP3A4

None

Lansoprazole None

Rabeprazole 2C8

Dexlansoprazole None

iv. Eliminationa. Extensively renal, changedb. Not dialyzablec. Half-life one to two hours

3 | R o g e r s

III. IndicationsA. Gastroesophageal reflux disease (GERD)13

i. Erosive esophagitis: eight week treatment courseii. Empiric treatment with PPI recommended in the setting of typical symptoms

a. Initiated once dailyb. Twice daily or change in PPI may be considered in non-responders

iii. Histamine H2 receptor antagonist (H2RA) may be used as maintenance optionin patients without erosive disease

iv. Maintenance PPI indicateda. Persistence symptoms after discontinuation of PPIb. Erosive diseasec. Barrett’s esophagus

B. Peptic Ulcer Disease i. Helicobacter pylori (H. pylori)14

a. PPI twice daily in combination with two antibioticsb. Length of therapy 7-14 days depending on regimen

ii. Non-steroidal anti-inflammatory drugs (NSAIDs)15

a. PPI may be used as primary preventionb. PPI may be discontinued once ulcer has healedc. Consider continuation of PPI if NSAIDs is necessary

C. Stress Ulcer Prophylaxis i. Recommended in intensive care unit (ICU) setting with risk factors16-17

a. Mechanical ventilation >48 hoursb. Coagulopathyc. Trauma/major burnsd. History of gastrointestinal (GI) bleed in past yeare. At least two of the following

1. Sepsis2. ICU stay more than seven days3. Occult GI bleeding for six or more days4. Glucocorticoid therapy (≥250mg hydrocortisone or

equivalent)ii. H2RA may be equal in efficacy and safety18

D. Triple oral antithrombotic therapy19 E. Acute GI bleed20

i. Treatment based on cause of ulcerii. Long term PPI treatment recommended for ulcers not due to H. pylori or

NSAIDs

Table 3. Duration of PPI13-20

Acute •Erosive esophagitis symptom relief•Duodenal/gastric ulcer•H. pylori infection•Stress ulcer prophylaxis in ICU•Triple oral antithrombotic

Chronic •Chronic GERD (confirmed via imaging)•Failure of step down therapy•Barrett's esophagus•Eosinophilic esophagitis•Chronic NSAIDs•GI bleed

4 | R o g e r s

IV. Adverse EffectsA. Common (1-10%)5-11

i. GI: abdominal pain, diarrhea, nausea, flatulenceii. Headache/dizziness

iii. Skin rashB. Thrombocytopenia21

i. Incidence: <1%ii. Immune mediated

C. Vitamin deficiencies22 i. Hypomagnesemia

ii. B12 deficiencyiii. Hypocalcemia

D. Infections i. Clostridium difficile23-24

a. H2RA: 53% increaseb. PPI: 74% increasec. Risk doubles with repeated dosingd. PPI use during treatment associated with 42% increase rate of

Clostridium difficile recurrenceii. Pneumonia25-27

a. Increased risk of nosocomial and community associatedb. Highest risk in first 30 days

E. Bone fracture28 i. Women’s Health Study (n=130,487)

a. Follow-up 7.8 yearsb. PPI associated with increased rate of spine, lower arm and total

fractures (HR 1.25, 95% CI 1.15-1.36)ii. FDA warning for hip, wrist and spine fractures for >50 years of age with

therapy for over one year or high doseF. Interstitial nephritis5

i. Incidence: <1%ii. Idiopathic hypersensitivity reaction

G. Rebound acid hypersecretion5 i. Incidence: 20%

ii. Decrease risk by using step down therapyH. Cardiovascular (CV) risk29

i. Concerning safety data submitted to Food and Drug Administration (FDA) in2007

ii. Omeprazole vs Surgery30

a. Investigators found 17 patients in the omeprazole group vs four in thesurgery group died of heart-related causes or had non-fatal myocardialinfarction (MI)

b. Surgery group was younger and healthieriii. Esomeprazole vs Surgery31

a. Initial data suggested difference in CV riskb. FDA’s analysis showed no significant difference (11 in the esomeprazole

group vs 10 in the surgery group)iv. FDA concluded long-term use is not likely to be associated with an increased

risk of heart problems and no changes in prescribing are warranted

5 | R o g e r s

Cardiovascular Risk Associated with PPI

I. PPI-clopidogrel interaction

A. Mechanism i. Inhibition of CYP2C19 blocks the conversion of clopidogrel to active drug

ii. Double-blind study showed reduced ex vivo antiplatelet effects of clopidogrel when combined with PPI32

B. Summary of trials i. In immediate period following acute coronary syndrome (ACS) or

percutaneous coronary intervention ii. Patients with CV risk factors

a. Coronary artery disease b. Diabetes c. Heart failure (HF)

Table 4. Clopidogrel-PPI Interaction Trials

Type of Trial Outcome

Supporting Interaction

Juurlink, et al. 200933

Observational N=2791 Three months

PPI (except pantoprazole) + clopidogrel had increased risk of reinfarction (OR 1.27, 95% CI 1.03-1.57) vs clopidogrel alone

Ho, et al. 200934

Retrospective cohort N=8205 2.5 years

PPI + clopidogrel increased risk of death or rehospitalization for ACS compared to clopidogrel alone.

PPI alone was not associated with increased risk compared to patients not taking either

CAPRIE/CREDO 2008 35

Post-hoc N=2116 CAPRIE: one year CREDO: 28 days and one year

CAPRIE: clopidogrel + PPI had elevated risk compared to clopidogrel alone. Worse outcomes with PPI+clopidogrel, but not PPI + ASA

CREDO: clopidogrel + PPI no significant increased risk but clopidogrel alone lowered risk. Increased risk in PPI + clopidogrel and PPI + placebo

Against Interaction

Rassen, et al. 200936

Observational N=64,561 Four years

PPI + clopidogrel vs clopidogrel alone MI 2.6% vs 2.1% (NS) Death 1.5% vs 0.9% (NS) Revascularization 3.4% vs 3.1% (NS)

O’Donoghue, et al. 200937

Post-hoc of PRINCIPLE-TIMI 44 (N=201) and TRITON-TIMI 38 (N=13,608) Six months

Mean platelet inhibition of either clopidogrel or prasaguel significantly lower in patients on a PPI at six hours post loading dose

No association between PPI use and increased primary endpoint (composite of CV death, MI, or stroke) in patients taking clopidogrel or prasugrel.

COGENT 201038

Randomized, placebo controlled N=3761 Six months

CV event rate Clopidogrel/PPI combo 4.9% Clopidogrel + placebo 5.7% HR: 0.99 (95% CI 0.68-1.44)

OR=Odds Ratio, CI=Confidence Interval, NS=Not Significant

6 | R o g e r s

II. The Verdict39 A. Population

i. Evaluation of 23 studies ii. Total of 222,311 patients

B. Objective i. Meta-analysis of major cardiovascular events

ii. Evaluate and compare CV risk of each PPI in combination with clopidogrel C. Results

i. CV risk significantly increased for several PPI in combination with clopidogrel a. Omeprazole b. Esomeprazole c. Lansoprazole d. Pantoprazole

ii. No difference in pantoprazole vs omeprazole, esomeprazole or lansoprazole iii. Meta-analysis of seven observational studies showed increased CV risk (HR:

1.28, 95% CI 1.14-1.44) with PPI compared to no clopidogrel/PPI therapy D. Author’s Conclusions

i. No difference seen in clinical outcome between different PPI in combination with clopidogrel

ii. Each PPI showed increased CV risk, but substantial heterogeneity present iii. Observation of increased risk with PPI alone indicates unmeasured confounders

or alternative mechanism

III. Clinical Implications

A. FDA’s reaction40 i. The concomitant use of omeprazole and clopidogrel should be avoided because

of the effect on clopidogrel's active metabolite levels and anti-clotting activity ii. Warning to avoid concomitant omeprazole or esomeprazole added to

clopidogrel prescribing information B. Concomitant use associated with decreased antiplatelet effects using platelet assays as

surrogate endpoints, but translation to clinically meaningful differences not established C. Observational studies and a single randomized control trial (RCT) have shown

inconsistent results.39 D. Unforeseen outcomes

i. Increase in CV events reported with medications not requiring activation a. Aspirin41 b. Ticagrelor42

ii. Increase in CV risk seen with PPI use alone39 IV. Clinical Question

A. Does PPI use alone increase risk of CV event independent of antiplatelet use? B. Which population does it affect?

i. With previous CV event ii. With CV risk factors

iii. Without CV risk factors

7 | R o g e r s

I. Asymmetric dimethylarginine (ADMA) dysregulation43

A. ADMA i. Associated with increased CV risk

ii. Endogenous competitive inhibitor of nitric oxide (NO) synthase (NOS) iii. Results in decreased NO loss of vasodilation and vasoprotective effects iv. Increase vascular inflammation and thrombosis v. Degraded by dimethylarginine dimethylaminohydrolase (DDAH)

B. PPI effect on ADMA i. PPI bind and inhibit DDAH

ii. Binding is reversible iii. PPI do not have to be in active form

Figure 2. ADMA Dysregulation Mechanism43

II. Increased homocysteine22,44 A. ↓ B12 absorption caused by PPI ↑homocysteine B. Homocysteine produced during ADMA synthesis C. Homocysteine inhibits DDAH reduction of NO

III. Negative inotropic effects45-46 A. Reduced contraction in isolated muscle strips of failing human hearts B. Dose-dependent C. Expression of gastric hydrogen-potassium adenosine triphosphatase in human

myocardium i. Reduced calcium flux from myocytes ii. Reduced calcium activated force from myofilaments

Mechanism for PPI Independent Increase in CV events

8 | R o g e r s

Literature Review

Juurlink DN, Dormuth CR, Huang A, et al. Proton pump inhibitors and the risk of adverse cardiac events. PLoS ONE. 2013;8(12):e84890.

Purpose To examine the potential association between PPI use and hospitalization for acute MI or HF

Design Self-matched case-series among residents in Ontario from January 1,1996 to December 31, 2008

Population Inclusion ≥66 years of age

Exclusion Hospitalized for less than three days

for MI Hospitalized for MI or HF less than

one year

Outcomes Primary: Risk of hospitalization for MI or HF following PPI initiation

Methods Demographics, medications, and physician services collected through national registries/databases

Follow up for 12 weeks o Index date: first date of PPI o Weeks 1-4: Risk interval o Weeks 5-8: Wash-out period o Weeks 9-12: Control interval

Secondary analysis o History of MI or HF (hospitalized 6-12 months prior the index date) o “Tracer” analysis with H2RA and benzodiazepines o Replicated analysis using two weeks vs four weeks for risk interval

Statistics o Fixed-effects logistic regression model o Replicated with random effects logistic regression model

Results Table 5. Demographics MI (5,550) HF (6,003)

Age (years) 77 80

Sex (% female) 49% 55%

Expired N (%) 956 (17.2%) 1235 (20.6%)

Table 6. Outcomes

Outcome Admission during Risk Interval (N)

Admission during Control Interval (N)

Odds Ratio (95% CI)

Primary

MI 2595 1439 1.8 [1.7 to 1.9]

HF 2713 1534 1.8 [1.7 to 1.9]

Secondary MI* 2039 1316 1.5 [1.4 to 1.7]

HF* 1985 1378 1.4 [1.3 to 1.5]

History of MI 175 85 2.1 [1.6 to 2.7]

History of HF 204 116 1.8 [1.4 to 2.2]

*excluding death in 12 week observation period

9 | R o g e r s

Table 7. Secondary “Tracer” Analysis

Outcome Admission during Risk Interval (N)

Admission during Control Interval

(N)

Odds Ratio (95% CI)

H2RA

MI* 2384 1336 1.8 [1.7 to 1.9]

HF* 1910 1287 1.5 [1.4 to 1.6]

Benzodiazepines MI* 2100 1569 1.3 [1.3 to 1.4]

HF* 2782 1760 1.6 [1.5 to 1.7]

*excluding death in 12 week observation period Secondary analysis

o Random effects model and two week time period analysis remained consistent with primary data

Conclusion Initiation of a PPI was found to be associated with a short-term risk of MI and HF, however, a risk of similar magnitude was seen with other medications suggesting that this does not reflect cause-and-effect

Critique Strengths Patients served as own control Real world practice setting

Limitations Assumed adverse effects more than

four weeks beyond index date were independent of PPI

Unknown adherence/drug dose No information on other CV disease

risk factors or NSAIDs use Only Ontario residents

Take Home Points

Short-term PPI was not associated with increased CV hospitalizations in patients with and without CV disease

Charlot M, Ahlehoff O, Norgard ML, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use. Ann Int Med. 2010;153:378-86.

Purpose To examine the risk of adverse CV outcomes related to concomitant use of PPI and clopidogrel versus PPI alone in adults hospitalized for MI

Design A nationwide cohort study in Denmark

Population Inclusion Discharge after initial MI from

2000-2006 Age: >30 years

Exclusion Previous MI Partially missing data Expired <30 days from MI

Outcomes Primary: Composite of rehospitalization for MI, stroke, or CV death Secondary: all-cause death, CV death, rehospitalization for MI, stroke or GI

bleed Methods Patients identified and information obtained through several national

registries with assessment points at 7, 14, 21 and 30 days after MI and one year total of follow-up

Collected information on medications obtained by patient after MI o All medications: 90 days o PPI and H2RA: one year

10 | R o g e r s

Statistics o Cox proportional hazards models to adjusted for several baseline

characteristics (concomitant medications, comorbid conditions, etc) o Quantified a propensity score for the likelihood of receiving a PPI in the

first year after discharge adjusted for same above baseline characteristics

o Additional: confounders effect size, type of PPI, dose-dependent o Sensitivity analysis of patients who survived 7, 14 and 21 days after MI

Results Included: 54,406 patients o Exclusions: 15,581 o Received clopidogrel: 24,702 (43.8%)

One or more concomitant PPI prescription: 6,753 (27.3%) Baseline

o Those on clopidogrel were younger, male, had less concomitant medical treatment, fewer comorbid conditions, more often PCI

o Those receiving PPI were older, female, more concomitant medications, more comorbid conditions

Primary outcome: 9,137 patients (16.2%) Table 8. Outcomes

Cox Proportional Hazards Regression Analysis

Propensity match

PPI + Clopidogrel vs Clopidogrel alone

1.29 [95% CI 1.17 to 1.42] 1.35 [95% CI 1.22 to 1.50]

PPI alone vs no clopidogrel

1.29 [95% CI 1.21 to 1.37] 1.43 [95% CI 1.34 to 1.53]

Effect of interaction of PPI and clopidogrel

0.98 [95% CI 0.88 to 1.10)

Reductions of GI bleed in clopidogrel patients

0.82 p=0.140

Risk remained with or without the presence of clopidogrel across all PPI medications

Risk remained with 7, 14 and 21 day sensitivity analysis

Conclusion PPI appears to be associated with a dose-independent increased risk for adverse CV outcomes regardless of clopidogrel use

Increased CV risk associated with PPI use caused by unmeasured confounders o Confounder would have to raise risk by 2.5-3 fold to explain results

Critique Strengths Large cohort PPI not available OTC during time

period Data collection with national

registry Previous MI excluded

Limitations Short follow-up Propensity match for significant

baseline differences Unmeasured confounders Biases from survival effects No information on adherence Non-US population

Take Home Points

In this retrospective trial, PPI use alone was found to have increased CV risk, however, unmeasured confounders and differences in baseline characteristics could have played a role

11 | R o g e r s

Shih CJ, Chen YT, Ou SM, et al. Proton pump inhibitor use represents an independent risk factor for myocardial infarction. Int J Cardio. 2014;177:292-7.

Purpose Examine the risk of MI in PPI users with no previous history of MI Design Propensity score-matching analyses and case-crossover analyses

Population Inclusion Prescribed PPI during ambulatory

visit between 2000-2009 Age: 18-80 years

Exclusion Prior MI Previous PPI within 120 days Hospitalized or blood transfusion

for GI bleed in prior 60 days

Outcomes Primary: Hospitalization for the incident MI

Methods Used the Longitudinal Health Insurance Database Propensity score-match

o Follow-up for 120 days after PPI prescription or till diagnosis of MI, expired, or lost to follow-up

o Multivariable logistic regression analysis Case-crossover study

o Index date: first day of hospitalization o Calculation of MI risk after PPI use o Controls

Negative: H2RA Positive: NSAIDs

o Compared exposed during 1-7 days prior to index date vs 8-14 days Additionally 1-14 days prior vs 15-28 days

o Conditional logistic regression model

Results Propensity score-match PPI users: 126,367 vs non-PPI users: 126,367

o PPI users: 79 (0.062%) vs non-PPI users: 50 (0.040%) developed MI Adjusted HR 1.58 [95% CI 1.11-2.25] Consistent across age, gender, DM, antiplatelet agents, NSAIDs

Case-crossover study Initial MI: 5,430

o Seven day window: Adjusted OR=4.61 [95% CI 1.76-12.07] o Fourteen day window: Adjusted OR=3.47 [95% CI 1.76-6.83]

NNH=4,357

Conclusion PPI use alone is associated with a greater risk of MI in patients with normal CV risk, but the benefit of PPI still far outweighs the adverse cardiovascular effects

Critique Strengths PPI limited to those with peptic

ulcer, duodenal ulcer, or endoscopy confirmed GERD

Case-crossover study reduces uncontrolled confounders

Negligible clopidogrel use

Limitations Propensity match for significant

baseline differences Obesity, smoking, ETOH, and family

history of coronary heart disease not available

Take Home Points

PPI use was associated with increased first time MI in two different study designs

Approximately 4,357 patients need to be treated with a PPI to cause one MI

12 | R o g e r s

Shah NH, LePendu P, Bauer-Mehren A, et al. Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS ONE. 2015;10(6): e0124653.

Purpose Examine if PPI may be associated with CV risk in the general US population Design Data-mining approach for pharmacovigilance on multiple electronic medical

record datasets and a prospectively followed cohort

Population Inclusion Diagnosis of GERD

Exclusion Age <18 years when first diagnosed

with GERD Outcomes Retrospective analysis: Occurrence of MI

Prospective analysis: CV mortality (death from MI, cardiac arrest, stroke, HF, or aneurysm rupture)

Methods Retrospective analysis o Data source

Stanford Translational Research Integrated Database Environment (STRIDE 1994-2011)

Practice Fusion, Inc (a free, web-based electronic health record system for clinicians 2007-2012)

Prospective survival analysis- GenePAD cohort (2004): o All patients with an elective, non-emergent coronary angiogram for

angina, SOB, or an abnormal stress test at Stanford or Mount Sinai Medical Centers

o Retrospective review and confirmed by next of kin o Examined H2RA as separate association

Data-mining approach utilized o False positive rate of 3.5% and false negative rate of 61%

Results Table 9. Outcomes

Stanford (N=70,477)

PPI Adjusted OR 1.16 [95% CI 1.09-1.24]

H2RA Adjusted OR 0.93 [95% CI 0.86-1.02]

Practice Fusion, Inc (N=221,438)

PPI Adjusted OR 1.19 [95% CI 1.09-1.30]

GenePad cohort (N=1503)

PPI

Unadjusted HR 2.22 [95% CI 1.19-4.16]

Adjusted HR 2.00 [95% CI 1.07-3.78]

H2RA

Unadjusted HR 1.05 [95% CI [0.15-7.59] Adjusted HR 1.00 [95% CI 0.14-7.26]

Stanford Only 6% of PPI and H2RA groups were also on clopidogrel Association persists after excluding clopidogrel and across age groups

GenePAD cohort Total 58 CV mortalities during median follow-up 5.2 years

Conclusion PPI appear to be associated with elevated risk of MI in the general population independent of clopidogrel use while H2RA do not have this risk

13 | R o g e r s

Critique Strengths Large, general population STRIDE more homogenous while

Practice Fusion more heterogeneous

Limitations Confounding factors such as obesity

and NSAIDs use Cannot account for OTC use Dose not taken into account Lack of clarity

Take Home Points

PPI, but not H2RA, were found to be associated with increased CV mortality in the general population through retrospective and prospective data-mining approaches

Conclusions

I. Hypothesis generating

A. True cause and effect? i. PPI users more likely to have other concomitant diseases associated with

increased CV risk ii. GERD confused for cardiac ischemia

B. Further investigation i. Prospective randomized trials needed

ii. May be unrealistic based on NNH of >4000

II. Clinical Implication A. Data thus far does not warrant any immediate action or changes to standard of care B. Continued diligence to reduce inappropriate PPI use

i. Frequent evaluation on the indication for PPI a. Prescribe the lowest effective dose for the shortest duration possible b. Consider step down therapy to H2RA if appropriate c. Risk vs benefit of long term use

ii. Education to providers and patients on OTC use

14 | R o g e r s

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