SEPPRMACI-ARM: Secondary Event Prevention Using Population Risk Management After PCI and for Anti-Rheumatic Medications

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02694185
• Collaborator: (none)
• Enrollment: 5,269
• Locations: 5
• Arms: 2
• Anticipated Duration (Months): 75
• Patients Per Site: 1053.8
• Patients Per Site Per Month: 14.1

Study Details

Study Description

Brief Summary

Ischemic heart disease (IHD) and its treatment carry profound public health and economic implications. Among Veterans, IHD represents one of the most common causes of death and disability, with over 500,000 affected individuals' annually. Rheumatic disease, though far less common than IHD can affect multiple organ systems and requires therapies costing in excess of $50,000 a year. Optimal treatment of Veterans with IHD and rheumatic disease requires a number of medications to maintain or improve health. Not taking medications as prescribed, however, is common and increases the risk of subsequent adverse events (cardiac death and myocardial infarction [MI]).

To improve medication adherence rates and the cardiac health of Veterans with IHD, the investigators propose to test a medication adherence intervention. Known as VA SEPPRMACI-ARM (Secondary Event Prevention using Population Risk Management After PCI and for Anti-Rheumatic Medications), this intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals if they have not refilled their medication a given number of days after it was due for refill. The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients not completing SMS and then IVR by not refilling their medication (or declining SMS and not completing IVR) escalate to a trained research interventionalist. The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient. The investigators will test the intervention on IHD patients who have recently undergone PCI-a cardiac procedure commonly used among IHD patients to improve the heart's blood flow and in patients starting anti-rheumatic medication. The investigators will test the intervention at four VA Cardiac Catheterization Laboratories (CCLs) and have 12 sites serving as usual care controls.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Ischemia; Rheumatic Diseases	Other: Caplan IVR	N/A

Detailed Description

Ischemic heart disease (IHD) and rheumatic diseases are both pervasive, expensive, and results in grave health consequences. IHD affects an estimated 15.4 million Americans 20 years of age-representing 6.4% of the adult population. The direct and indirect cost of IHD has been estimated at $195.2 billion, with a doubling of cost projected by 2030.5 Similarly, the direct cost to the U.S. workforce for rheumatoid arthritis alone approaches $5.8 billion yearly.

Widely-accepted national evidence-based guidelines support the use of cardio-protective medications to reduce the risk of adverse consequences resulting from IHD and disease modifying anti-rheumatic medications (DMARDs) to reduce the risk of adverse consequence in rheumatic diseases. For example, numerous rigorously conducted randomized trials show that statins improve outcomes and reduce mortality in patients with established cardiovascular disease (i.e., secondary prevention), including those undergoing percutaneous coronary interventions (PCI). The use of statins and beta-blockers have been repeatedly demonstrated to be cost-effective in lowering cardiovascular event (CVE) rates, in part by their effects on cholesterol, and blood pressure, respectively. Accordingly, the most recent VA performance measures and American Heart Association guidelines encourage the use of statins in patients with atherosclerotic disease; beta-blockers in subjects with left ventricular systolic dysfunction (ejection fraction less than 40%), prior MI, or blood pressure of 140/90 or greater; and clopidogrel following any acute coronary syndrome (ACS) or PCI with stent. The rheumatology literature provides similar evidence for the benefit of DMARDs in rheumatic diseases, and guidelines strongly endorse their use.

Unfortunately, non-adherence to medications is common, and increases the risk of poor outcomes. The investigators' 2011 national preliminary data from VA cardiac catheterization laboratories (CCLs) demonstrate that over 6300 patients experienced at least one refill gap of >= 7 days for statins in the year following PCI. The mean proportion of days covered (PDC) for these patients was only 75%-below the PDC threshold of 80% that typical defines adherent patients, based on the empiric evidence for effectiveness of medications at this cut-point. Non-adherent patients were present at all CCLs without substantial variation in mean PDC by center, suggesting a global problem.

Systematic problems underlie and contribute to non-adherence to medications. Usual care of

IHD and rheumatic disease patients is encumbered by systematic deficiencies including:

passive monitoring (contact with patients only when initiated by the patient) and inefficiency (time-consuming patient-by-patient approach, rather than through population management). The proposed intervention addresses both the complex patient-specific factors (emphasizing forgetfulness and carelessness) and the systematic inadequacies using a multi-modal, escalating approach.

Objectives

1. To assess the effectiveness of a multi-faceted patient-centered intervention versus usual care in improving medication adherence as measured by proportion of days covered (PDC, primary outcome). This will be tested among IHD patients for statins, beta-blockers and clopidogrel in the year after PCI and among rheumatology clinic patients chronically prescribed DMARDs. Hypothesis: The PDC for patients in the intervention arm will exceed the PDC for the usual care arm by a 10% absolute difference.

2. (Secondary outcome): To determine the effectiveness of a multi-faceted patient-centered intervention versus usual care in reducing secondary CVEs (myocardial infarction [MI], repeat revascularization [PCI or coronary bypass graft], and all-cause mortality) among IHD patients at 18 months post-PCI and progressive erosive disease demonstrated on plain film radiographs in patients with rheumatic diseases (i.e. "radiographic progression"). Hypothesis: The rate of CVEs and radiographic progression will be 5% relatively lower for patients in the intervention arm compared with usual care.

3. (Secondary outcome): To establish the cost to implement and maintain the intervention, above the cost of usual care, as well as the incremental cost effectiveness (ICE; e.g. cost to achieve at 10% improvement in PDC; cost per CVE prevented). Hypothesis: This aim does not posit a hypothesis as the objective is descriptive. The available funding for this project limits this outcome to IHD patients (no rheumatic disease patients will be analyzed according to cost).

Study Design

• Study Type: Interventional
• Actual Enrollment: 5269 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Health Services Research
• Official Title: Secondary Event Prevention Using Population Risk Management After PCI
• Actual Study Start Date: Oct 1, 2016
• Actual Primary Completion Date: Dec 31, 2019
• Anticipated Study Completion Date: Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Group This group will undergo the intervention as described in the protocol	Other: Caplan IVR; This intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients have not refilled their medication more than 4 or 7 days after it was due to be refilled). The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients failing SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient.
No Intervention: Control Group This group will not receive the intervention, they will receive usual care

Outcome Measures

Primary Outcome Measures

1. Proportion of Days Covered (PDC) [1 year]

   Proportion of Days Covered (PDC) is measured by looking at the number of doses of medication a patient has versus days in the month (if a patient has 20 days of medication for a 30 day period their PDC is 20/30, 2/3, or 66.7%). Used to assess the effectiveness of the intervention, PDC will be tested among IHD patients in the year after PCI and among rheumatology clinic patients chronically prescribed DMARDs.

Secondary Outcome Measures

1. Cardiovascular Events (CVE) [1 year]

   Cardiovascular Events (CVEs) such as mortality, myocardial infarction, stroke, or repeat revascularization among IHD patients at 12 months post-PCI and progressive erosive disease demonstrated in patients with rheumatic disease will be monitored. CVEs will be monitored to determine if there is a reduction in the occurrence of those events as a result of the intervention.

2. Incremental Cost Effectiveness (ICE) [through study completion, an average of 1 year]

   To establish the cost to implement and maintain the intervention, above the cost of usual care. Incremental Cost Effectiveness (ICE) is the cost to achieve a 10% improvement in PDC, and the cost of CVE prevented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 95 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Patients will qualify for inclusion if they:

1. Undergo PCI or are prescribed a DMARD.

2. Are prescribed any of the following medications:

[for the IHD intervention]

• Statin

• Beta-blocker

• Thienopyridines (dual platelet inhibitors)

[for the DMARD intervention]

• Oral methotrexate

• Sulfasalazine

• Azathioprine

• Leflunomide

• Tofacitinib

• Hydroxychloroquine [Note: as a study focused on adherence, the investigators will NOT address the appropriateness of prescribed medications, which is an important, but separate issue]

1. Receive their care from the VA. This is defined by the presence of a VA-assigned-PCP in the year prior to PCI or in the year following PCI (IHD intervention) or in the year prior to or following index DMARD prescription (rheumatic disease intervention).

Exclusion Criteria:

Patients will be excluded under the following circumstances:

• Undergoing only diagnostic (non-interventional) catheterization

• Receive their index medicines (listed in item above) from a non-VA source

• Discharge to nursing home or skilled nursing facility

• Individuals with impaired decision making capacity

• Prisoners

• Pregnant women

• The terminally ill

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Francisco VA Medical Center, San Francisco, CA	San Francisco	California	United States	94121
2	Rocky Mountain Regional VA Medical Center, Aurora, CO	Aurora	Colorado	United States	80045
3	Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD	Baltimore	Maryland	United States	21201
4	Durham VA Medical Center, Durham, NC	Durham	North Carolina	United States	27705
5	VA Caribbean Healthcare System, San Juan, PR	San Juan		Puerto Rico	00921

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Liron Caplan, MD PhD, Rocky Mountain Regional VA Medical Center, Aurora, CO

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 6, 2019

More Information

Publications

• Baker JF, Sauer B, Teng CC, George M, Cannon GW, Ibrahim S, Cannella A, England BR, Michaud K, Caplan L, Davis LA, O'Dell J, Mikuls TR. Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis Is Associated With Changes in Blood Pressure. J Clin Rheumatol. 2018 Jun;24(4):203-209. doi: 10.1097/RHU.0000000000000736.
• Daniel CM, Davila L, Makris UE, Mayo H, Caplan L, Davis L, Solow EB. Ethnic Disparities in Atherosclerotic Cardiovascular Disease Incidence and Prevalence Among Rheumatoid Arthritis Patients in the United States: a Systematic Review. ACR Open Rheumatol. 2020 Sep;2(9):525-532. doi: 10.1002/acr2.11170. Epub 2020 Sep 1.
• Hirsh J, Wood P, Keniston A, Boyle D, Quinzanos I, Caplan L, Davis L. Universal Health Literacy Precautions Are Associated With a Significant Increase in Medication Adherence in Vulnerable Rheumatology Patients. ACR Open Rheumatol. 2020 Feb;2(2):110-118. doi: 10.1002/acr2.11108. Epub 2020 Jan 19.
• McCulley CB, Barton JL, Cannon GW, Sauer BC, Teng CC, George MD, Caplan L, England BR, Mikuls TR, Baker JF. Body mass index and persistence of conventional DMARDs and TNF inhibitors in rheumatoid arthritis. Clin Exp Rheumatol. 2019 May-Jun;37(3):422-428. Epub 2018 Nov 7.
• Raghavan S, Liu WG, Berkowitz SA, Barón AE, Plomondon ME, Maddox TM, Reusch JEB, Ho PM, Caplan L. Association of Glycemic Control Trajectory with Short-Term Mortality in Diabetes Patients with High Cardiovascular Risk: a Joint Latent Class Modeling Study. J Gen Intern Med. 2020 Aug;35(8):2266-2273. doi: 10.1007/s11606-020-05848-5. Epub 2020 Apr 24.
• Raghavan S, Liu WG, Michael Ho P, Plomondon ME, Barón AE, Caplan L, Joynt Maddox KE, Magid D, Saxon DR, Voils CI, Bradley SM, Maddox TM. Coronary artery disease severity modifies associations between glycemic control and both mortality and myocardial infarction. J Diabetes Complications. 2018 May;32(5):480-487. doi: 10.1016/j.jdiacomp.2018.01.010. Epub 2018 Jan 31.
• Yazdany J, Caplan L, Fitzgerald J, Schmajuk G. Editorial: The Evolving Art and Science of American College of Rheumatology Guidelines. Arthritis Rheumatol. 2019 Jan;71(1):2-4. doi: 10.1002/art.40725. Epub 2018 Nov 30.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02694185
• Other Study ID Numbers: IIR 14-048; 16-1419; 1I01HX001604-01A2
• First Posted: Feb 29, 2016
• Last Update Posted: Mar 23, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by VA Office of Research and Development: Medication Adherence; Randomized Controlled Trial; Veterans
• Additional relevant MeSH terms: Rheumatic Diseases; Myocardial Ischemia; Collagen Diseases; Ischemia

Study Results

Participant Flow

Recruitment Details

This study will employ an approach to consent similar to SDP-179 Hybrid Effectiveness-Implementation Study to Improve Clopidogrel Adherence which has previously been approved by (CIRB Protocol #12-12). The study will enroll all subjects undergoing PCI or using DMARDs at 16 VA Medical Centers. These Medical Centers are all tertiary referral hospitals within their respective VISN and provide a full spectrum of cardiac and rheumatologic care services.

Arm/Group Title	Experimental Group	Control Group
Arm/Group Description	This group will undergo the intervention as described in the protocol Caplan IVR: This intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients have not refilled their medication more than 4 or 7 days after it was due to be refilled). The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients failing SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient.	This group will not receive the intervention, they will receive usual care
Period Title: Overall Study
STARTED	476	4793
COMPLETED	431	4793
NOT COMPLETED	45	0

Baseline Characteristics

Arm/Group Title	Experimental Group	Control Group	Total
Arm/Group Description	This group will undergo the intervention as described in the protocol Caplan IVR: This intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients have not refilled their medication more than 4 or 7 days after it was due to be refilled). The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients failing SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient.	This group will not receive the intervention, they will receive usual care	Total of all reporting groups
Overall Participants	431	4793	5224
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	68.6	68.7	68.7
Sex: Female, Male (Count of Participants)
Female	12 2.8%	103 2.1%	115 2.2%
Male	419 97.2%	4690 97.9%	5109 97.8%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	330 76.6%	3789 79.1%	4119 78.8%
African American	89 20.6%	872 18.2%	961 18.4%
Other	12 2.8%	132 2.8%	144 2.8%
Region of Enrollment (Count of Participants)
Puerto Rico	42 9.7%	214 4.5%	256 4.9%
United States	389 90.3%	4579 95.5%	4968 95.1%

Outcome Measures

1. Primary Outcome

Title	Proportion of Days Covered (PDC)
Description	Proportion of Days Covered (PDC) is measured by looking at the number of doses of medication a patient has versus days in the month (if a patient has 20 days of medication for a 30 day period their PDC is 20/30, 2/3, or 66.7%). Used to assess the effectiveness of the intervention, PDC will be tested among IHD patients in the year after PCI and among rheumatology clinic patients chronically prescribed DMARDs.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Participant numbers differ below because not all subjects are taking an anti-platelet, beta-blocker, and statin medication.

Arm/Group Title	Experimental Group	Control Group
Arm/Group Description	This group will undergo the intervention as described in the protocol Caplan IVR: This intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients have not refilled their medication more than 4 or 7 days after it was due to be refilled). The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients failing SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient.	This group will not receive the intervention, they will receive usual care
Measure Participants	431	4793
Anti-platelet	82.6	75.6
Beta-Blocker	78.4	73.3
Statin	78.8	71.2

2. Secondary Outcome

Title	Cardiovascular Events (CVE)
Description	Cardiovascular Events (CVEs) such as mortality, myocardial infarction, stroke, or repeat revascularization among IHD patients at 12 months post-PCI and progressive erosive disease demonstrated in patients with rheumatic disease will be monitored. CVEs will be monitored to determine if there is a reduction in the occurrence of those events as a result of the intervention.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Group	Control Group
Arm/Group Description	This group will undergo the intervention as described in the protocol Caplan IVR: This intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients have not refilled their medication more than 4 or 7 days after it was due to be refilled). The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients failing SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient.	This group will not receive the intervention, they will receive usual care
Measure Participants	431	4793
Mean (95% Confidence Interval) [Cardiovascular events]	15.2	14.3

3. Secondary Outcome

Title	Incremental Cost Effectiveness (ICE)
Description	To establish the cost to implement and maintain the intervention, above the cost of usual care. Incremental Cost Effectiveness (ICE) is the cost to achieve a 10% improvement in PDC, and the cost of CVE prevented.
Time Frame	through study completion, an average of 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Group	Control Group
Arm/Group Description	This group will undergo the intervention as described in the protocol Caplan IVR: This intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients have not refilled their medication more than 4 or 7 days after it was due to be refilled). The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients failing SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient.	This group will not receive the intervention, they will receive usual care
Measure Participants	431	4793
Median (Inter-Quartile Range) [dollars per patient]	821.45	893.55

Adverse Events

Time Frame	Adverse event data were collected beginning from enrollment to study completion; average duration per participant was one year, per the design of the study.
Adverse Event Reporting Description	Over the duration of the entire study, there have been 23 patients who passed away in the intervention group. The Data Safety Monitoring Board did not attribute any deaths to their participation in the research or the intervention.
Arm/Group Title	Experimental Group		Control Group
Arm/Group Description	This group will undergo the intervention as described in the protocol Caplan IVR: This intervention will consist of: proactive real-time adherence monitoring of patients and targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients have not refilled their medication more than 4 or 7 days after it was due to be refilled). The intervention will employ a tailored, escalating-intensity approach which begins with some combination of personalized short messaging service (SMS) text messages and interactive voice response (IVR) telephone technology, depending on patient preference. Patients failing SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will contact the patient and address adherence barriers based on the dimensions outlined by the World Health Organization (WHO) that are specific to each patient.		This group will not receive the intervention, they will receive usual care
All Cause Mortality
	Experimental Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/476 (4.8%)		209/4793 (4.4%)
Serious Adverse Events
	Experimental Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/476 (0%)		0/4793 (0%)
Other (Not Including Serious) Adverse Events
	Experimental Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/476 (0%)		0/4793 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.