Development of Diagnostic Criteria for Serious Non-AIDS Events in HIV Clinical Trials

Abstract

Purpose

Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial.

Methods

SNA definitions were developed based upon the following: (1) criteria from a previous trial (SMART), (2) review of published literature, (3) an iterative consultation and review process with the ERC and other content experts, and (4) evaluation of draft SNA criteria using retrospectively collected reports in another trial (ESPRIT).

Results

Final criteria are presented for acute myocardial infarction, congestive heart failure, coronary artery disease requiring drug treatment, coronary revascularization, decompensated liver disease, deep vein thrombosis, diabetes mellitus, end-stage renal disease, non-AIDS cancer, peripheral arterial disease, pulmonary embolism, and stroke. Of 563 potential SNA events reported in ESPRIT and reviewed by an ERC, 72% met “confirmed” and 13% “probable” criteria. Twenty-eight percent of cases initially reviewed by the ERC required follow-up discussion (adjudication) before a final decision was reached.

Conclusion

HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication.

With the decline in AIDS-related events and deaths due to highly active antiretroviral therapy (HAART), there is greater recognition of serious non-AIDS (SNA) diseases as important clinical outcomes in HIV-infected persons, including those on antiretroviral therapy (ART).^1–4 Analyses of mortality among HIV-infected patients in the era of HAART have reported increases in the proportion of deaths due to non-AIDS related conditions, including cardiovascular disease (CVD), liver disease, and non-AIDS defining cancers.^1,5–10 The importance of including such events was shown in the Strategies for Management of Antiretroviral Therapy (SMART) clinical trial.^11,12 Although it was thought that continuous ART might be associated with an increased risk of certain SNA events because of treatment-related toxicity, CD4-guided treatment interruption was instead associated with an increased risk of major cardiovascular, renal, or hepatic disease.

HIV-infected patients, including those on HAART, may develop a variety of SNA events. HIV infection or use of antiretroviral drugs may contribute to increased CVD risk,^13,14 and use of effective HAART has resulted in increasing numbers of aging HIV-infected patients who may develop metabolic syndrome or who may have other CVD risk factors.¹⁵ HIV-infected patients on HAART may be more prone to insulin resistance and frank diabetes, which may predispose patients to CVD as well as other diabetes-related complications.^9,16,17 Insulin resistance and diabetes may be due to a variety of factors including underlying HIV infection, different antiretroviral drugs, and treatment-associated weight gain. ¹⁷ Current diabetes has been identified has a risk factor for death in HIV-infected persons.⁹

The risk of deep venous thrombosis (DVT) may be greater in HIV patients than in the general population,¹⁸ which in turn presents a risk for pulmonary embolism. Potential pathogenic mechanisms include a progressive prothrombotic state associated with advancing HIV disease or endothelial cell activation.^19,20

The incidence of a number of non-AIDS malignancies in HIV-infected subjects is higher than in HIV-uninfected controls or the general population.^21,22 Although some of these cancers are associated with coinfections from other viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus, or Epstein-Barr virus,^23–25 HIV-infected patients are also at increased risk for other malignancies such as lung cancer.²⁶ Patients with HIV, especially those coinfected with HBV and HCV, are at increased risk for cirrhosis, liver cancer, and end-stage liver disease with hepatic failure.^25,27,28 HIV-infected patients may also develop a variety of kidney diseases, such as HIV-associated nephropathy, which can lead to end-stage renal disease.^29–31

The risk for a number of SNA events is increased with lower CD4+ counts and uncontrolled HIV replication and may be decreased with effective HAART.^{3,4,10–12,32–34} Although many HIV studies have used surrogate laboratory endpoints such as CD4+ lymphocyte count or HIV viral load, the benefit of an HIV intervention on a surrogate laboratory marker such as CD4+ count does not necessarily translate into a benefit on clinical outcome.^35–39 For large HIV randomized trials evaluating new treatment strategies or new types of therapy, development of clinical diseases still represent important and definitive endpoints.

With the growing recognition of SNA events as significant clinical outcomes that may be affected by HIV therapy, it is important that these be identified and evaluated in trials of various HIV treatment strategies. If HIV clinical trials are to include SNA events as clinical outcomes, it is important to have standardized criteria and procedures for event reporting and verification. Using objective and standardized criteria, the reportable events can then be reviewed by an independent Endpoint Review Committee (ERC), blinded to treatment status.^40–42 Such an independent evaluation is especially critical in open-label studies where investigators may be biased by knowledge of treatment assignment.

In preparation for a large multicenter, international HIV clinical trial (Strategic Timing of Antiretroviral Treatment, or START), we undertook a comprehensive process to develop standardized criteria and procedures for reporting and review of 12 SNA events. While final SNA definitions for START were being developed, we used draft criteria for 7 events to retrospectively review SNA cases in another clinical trial, the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT).³⁸ This article reports how the process of creating SNA event criteria was conducted, results of our application of interim definitions to the ESPRIT study, and the final SNA event criteria that were developed.

METHODS

START Study

START is an international randomized trial that compares immediately starting ART in persons with a CD4+ count above 500 cells/mm³ to waiting until the CD4+ count is <350 cells/mm³. The primary composite endpoint is the development of a serious AIDS event as defined in the protocol, death from any cause, or development of one of the following SNA events: acute myocardial infarction (AMI), stroke, coronary revascularization (reflecting coronary artery disease [CAD] requiring a therapeutic procedure), end-stage renal disease (ESRD), decompensated liver disease, and non-AIDS–defining cancers (excluding basal and squamous cell skin cancers unless they result in death). Secondary endpoints also include the following SNA events: pulmonary embolism, congestive heart failure (CHF), CAD requiring drug treatment, new onset diabetes mellitus, peripheral arterial disease, and DVT. The START planning committee selected these SNA events as primary or secondary clinical endpoints of particular interest for this study after a thorough process of discussion, consultation with other HIV experts, review of the data from SMART and other relevant studies from the HIV literature, and consideration of many of the issues described previously.

The START protocol calls for each of these 12 SNA events to be reported on a standardized case report form and to be reviewed by an ERC. The process of developing case definitions for these events included 4 components: (1) review of SNA definitions used for another clinical trial (SMART), (2) review of the literature for clinical criteria guidelines, (3) an iterative process of consultation and review with the ERC and other content experts, and (4) evaluation of draft SNA criteria and the proposed SNA review processes in a retrospective review of 7 events for another ongoing study (ESPRIT). Each of these components is described below.

SNA Event Criteria for SMART

In SMART, clinical investigators reported a variety of “supplemental events.” These included diseases felt indicative of major cardiovascular, renal, or hepatic disease (such as AMI, stroke, CAD requiring surgery, cirrhosis, and kidney failure), as well as non-AIDS–defining cancers.^11,43 Case definitions used for these SNA events in SMART were reviewed.

Review of the Literature for Clinical Criteria Guidelines

A full list of all articles and clinical algorithms consulted is beyond the scope of this article, but several are mentioned as illustrative examples. In 2007, a European Society of Cardiology, American College of Cardiology, World Heart Federation, and American Heart Association task force developed a “universal definition of myocardial infarction”⁴⁴; this definition was heavily utilized in creating the “confirmed” criteria for AMI. In developing criteria for diabetes mellitus, we consulted guidelines for “Diagnosis and Classification of Diabetes Mellitus,” published by the American Diabetes Association.⁴⁵ In formulating criteria for DVT, we drew upon the clinical prediction rule developed Wells and colleagues.⁴⁶

Review and Comment by ERC and Other Content Experts

Initial draft definitions for SNA events were developed by the ERC Chair and Co-Coordinators and were sent by e-mail for review by ERC members, who included HIV-experienced clinicians plus cardiologists and neurologists. Draft definitions were also sent to members of specific interest groups in the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) network, which is coordinating the START trial. These interest groups included CVD, liver disease, renal disease, neurology, and malignancy groups. Reviewers exchanged opinions by e-mail, and draft criteria were revised in response to reviewer comments. SNA event criteria include both “confirmed” criteria, which reflected a higher degree of diagnostic certainty and often included histologic or other laboratory documentation, and “probable”” criteria, which usually included combinations of clinical criteria and other less definitive diagnostic findings.

Use of Draft SNA Criteria and Review Process in ESPRIT Study

In 2006, results from SMART reinforced the importance of SNA events as study outcomes.^11,12 Data analysis plans for the then ongoing ESPRIT study were subsequently modified to include a formal review of whether 1 of 7 SNA events had occurred. ESPRIT was a randomized trial of interleukin-2 plus HAART versus HAART alone in patients with CD4+ counts ≥300 cells/mm³.³⁸ All sites were asked to retrospectively review their records for possible cases of these 7 SNA events: AMI, stroke, CAD requiring a therapeutic procedure (invasive or surgical), cirrhosis, ESRD, non-AIDS malignancy, and pulmonary embolism. If identified, they were asked to send the case report form and supporting source documentation to the ESPRIT Data Management and Coordinating Center. This process allowed us not only to collect additional information for ESPRIT but also to evaluate draft definitions that were being considered for START.

The process for reporting and review of SNA events was adapted from that used for AIDS-related events in ESPRIT. Each site investigator who identified an SNA event completed a standardized clinical event form and submitted this form along with supporting source documentation. Non-English narratives and supporting source documents had to be translated, and normal value ranges were requested for laboratory reports. Reported events with supporting documentation were then reviewed by the ERC, blinded to treatment arm, and classified as “confirmed,” “probable,” or “does not meet criteria” based upon the criteria that were being used at that time.

The SNA definitions used by ESPRIT investigators for reporting events and the ERC for reviewing events were very similar to the final SNA criteria reported in this article, except where otherwise noted (specific details on these interim criteria are available from the authors). Each event was sent to 3 reviewers; if all reviewers did not agree on the diagnostic certainty classification, a process of adjudication among the 3 (typically by e-mail) occurred until consensus was reached. An ERC Nurse Coordinator managed the flow of information and tracked the status of each reported event to help ensure that it was reviewed in a timely manner.

Development of Final SNA Criteria

After the ESPRIT SNA event review, criteria were finalized for AMI, stroke, coronary revascularization, non-AIDS malignancy, pulmonary embolism, and ESRD. The START Planning Group decided to change “cirrhosis”” to “decompensated liver disease” (reflecting greater severity) as the reportable SNA event for ERC review. The Planning Group also added 5 new SNA events for ERC review: CHF, CAD requiring drug treatment, diabetes mellitus, peripheral arterial disease, and DVT. Using the iterative review and consultation processes described previously, final criteria were ultimately developed for all 12 SNA events.

Quality Control Measures

A number of quality control measures were implemented for START for reporting of SNA events; these were adapted from those used as part of the reporting and review process for AIDS events in ESPRIT.⁴¹ All participating sites and site investigators have access to the specific diagnostic criteria and reporting standards for each clinical event; these are also available on the study’s Web site. Training is provided to all site investigators on the reporting and review processes, including required documentation.

Each SNA event has a separate case report form, filled in by the local investigator; a copy of one such form is included as Figure A1 in the Appendix. This form includes a listing of each of the diagnostic criteria for that event. For each of these criteria, the investigator is asked to report whether the supporting documentation has been submitted, whether it is pending, or whether it will never be available. If not available, the site is asked to indicate the reason why. This allows us to distinguish whether documentation will never be available or if it is available (and has been requested) but not yet received. Because some study participants receive their primary medical care at a site different from the site where they are enrolled for the study, investigators work with primary care providers to obtain and make available all relevant information and documentation.

Figure A1.

Sample case report form

All completed forms with documentation are first sent to regional International Coordinating Centers, where they are reviewed for completeness. Sites with incomplete information are contacted to obtain follow-up information. Completed materials are then sent to the INSIGHT Statistical and Data Management Center, where they undergo a second level of review by the ERC coordinator. The case report form and supporting documentation are finally forwarded to the ERC for review. If follow-up information is received after the ERC initially reviews a case, this follow-up information is sent to the ERC and the case is re-reviewed. All sites are routinely monitored with review of medical records to ensure that report forms have been completed for clinical events that should be reported.

RESULTS

ESPRIT Retrospective Review

In ESPRIT, 563 SNA events were reported for 4,150 HIV-infected persons enrolled. These 563 events included 83 (15%) reports of AMI, 56 (10%) of cirrhosis, 92 (16%) of CAD requiring a therapeutic procedure, 1 (<1%) of ESRD, 270 (48%) of non-AIDS malignancies, 23 (4%) of pulmonary embolism, and 38 (7%) of stroke (Table 1). Of the total events reported, 483 (86%) were supported by the ERC after review as meeting “confirmed” (407 events, 72%) or “probable” (76 events, 13%) criteria, and 80 events (14%) were classified as “does not meet criteria.” Of the 56 cases of cirrhosis, the ERC was able to classify 27 (48%) as also having decompensated liver disease.

Table 1.

Reported serious non-AIDS events in ESPRIT and classification by Endpoint Review Committee in meeting diagnostic categories

Serious non-AIDS event	Final outcome of review			Adjudicated
	Confirmed	Probable	Does not meet criteria
AMI (n = 83)	55 (66%)	3 (4%)	25 (30%)	33 (40%)
Cirrhosis (n = 56)	17 (30%)	22 (39%)	17 (30%)	33 (59%)
CAD requiring therapeutic procedure (n = 92)	85 (92%)	—a	7 (8%)	10 (11%)
ESRD (n=1)	1 (100%)	—a	0 (0%)	—
Non-AIDS malignancy (n = 270)	211 (78%)	46 (17%)	13 (5%)	57 (21%)
Pulmonary embolism (n = 23)	17 (74%)	3 (13%)	3 (13%)	7 (30%)
Stroke (n = 38)	21 (55%)	2 (5%)	15 (39%)	14 (37%)
Total (n = 563)	407 (72%)	76 (13%)	80 (14%)	155 (28%)

Note: AMI = Acute myocardial infarction; CAD = coronary artery disease; ESRD = end-stage renal disease

^aNot applicable.

The number and proportion of reported events that were determined by the ERC as meeting various diagnostic criteria are summarized in Table 1. The proportion of reported cases that were ruled out as “does not meet criteria” were highest for stroke (39%), AMI (30%), and cirrhosis (30%); excluding ESRD, the proportion was lowest for malignancies (5%) and CAD requiring a therapeutic procedure (8%). An additional question on the ERC review form asked reviewers if they thought there was adequate information and supporting documentation to make a decision on diagnostic certainty. Of 80 events classified as “does not meet criteria,” one or more of the reviewers felt that information or supporting documentation was inadequate for 63 (79%) events.

Of the 563 events reported to the ERC, 155 (28%) were adjudicated because of an initial disagreement by the 3 reviewers about the classification of diagnostic certainty. In all cases, these initial differences were resolved among the 3 reviewers through follow-up discussions. Excluding ESRD, the proportion of all cases that required follow-up adjudication was greatest for cirrhosis (59%) followed by AMI (40%) and lowest for CAD requiring therapeutic procedure (11%) followed by non-AIDS malignancy (21%).

Final Diagnostic Criteria

Criteria were ultimately developed for 12 SNA events and are listed in the Appendix. Ten of these events had both “confirmed” and “probable” criteria, and 2 events had only “confirmed” criteria. Six of these represented SNA events used in the ESPRIT retrospective review, and for 5 the final “confirmed” and “probable” criteria remained relatively unchanged; the criteria for ESRD were expanded from “confirmed” only to both “confirmed” and “probable.” The START planning committee decided to substitute “decompensated liver disease” for “cirrhosis,” requiring modification of the case definition. Five additional SNA events were added to the final list.

DISCUSSION

This article describes the process of development of clinical criteria for SNA events being used in the START HIV clinical trial as one of the major components of the primary composite endpoint, as well as for secondary endpoints. We also report the results of our application of interim SNA definitions to another HIV clinical trial (ESPRIT) and our final “confirmed” and “probable” criteria for these events.

In the ESPRIT trial, which enrolled patients with ≥300 CD4+ cells, the number of SNA events meeting case criteria was greater than the number of reported AIDS-defining events and opportunistic infections. Although SNA events may occur across a range of CD4+ counts, the risk for a number of SNA events is increased with lower CD4+ counts and uncontrolled HIV replication and may be decreased with effective HAART.^{3,4,10–12,32–34} A decrease in SNA events is an important consideration in recommendations for earlier initiation of ART.^3,4 In addition, a number of SNA diseases may be associated with toxicities of specific ART drugs; these include CVD,^47,48 renal disease,⁴⁹ and diabetes,⁵⁰ among others.

For all these reasons, there is a compelling case for including SNA events in HIV trials that have clinical morbidity and mortality as outcome measures.

There are a number of reasons why many large HIV clinical trials have used standardized clinical criteria for AIDS-defining events, with independent review by an ERC blinded to treatment status.^{11,38,41,42,51} Because investigators may have different standards for determining whether a specific clinical event has occurred, the use of uniform criteria provides greater consistency between sites and allows those evaluating results of a trial to know the basis for determining whether a specific disease outcome occurred. Independent review by an ERC is especially important in open-label trials where investigators may be biased by knowledge of treatment assignment. The same principles should hold for HIV clinical trials evaluating SNA events as part of the major clinical endpoints.

Although review of clinical information for some SNA events may be relatively unambiguous (such as a pathology report or procedure note), the interpretation of other data may be less straightforward, and expert evaluation and clinical judgment are required. Even with prespecified protocol criteria, our experience is that there are cases where different experts may have slightly different interpretations based on the medical history and supporting source documentation. In ESPRIT, although 28% of all reported SNA events required adjudication, in all cases this process resulted in a consensus decision. We believe this process of dialog and discussion among reviewers helps to ensure the most careful and conscientious decision concerning whether a reported case meets a standardized definition and serves to strengthen the precision and quality of our endpoint information. This also supports the importance of having ERC members with specific content expertise in the clinical syndromes being reviewed.

In our ESPRIT review of SNA events, 14% of all reported cases were classified by the ERC as “does not meet criteria.” There are at least 2 major reasons why a case may have been classified as “does not meet criteria.” Clinical trial investigators were encouraged to submit reports on all potential SNA events, even if they were uncertain. In some cases, full information and documentation were appropriately supplied, and the ERC, after reviewing all data, concluded that case criteria were not fulfilled. In other cases, reported events were classified “does not meet criteria” because of incomplete information; in 79% of cases ruled out (or 11% of all reported cases), one or more reviewers felt that clinical information or supporting documentation were inadequate.

Although the retrospective nature of SNA data collection in ESPRIT may have made it more difficult to obtain all relevant information and documentation, our results reinforce that the ERC must have access to a good clinical history and adequate supporting source documentation to make the most informed judgment. For some diagnostic studies, the ERC may want copies of the actual test performed (such as electrocardiograms) or results of interpretation by a specialist (such as a complete report by a radiologist). Participating sites in clinical trials should have access to the specific diagnostic criteria and reporting standards for each clinical event, and local investigators should be trained on the importance of providing complete clinical information and documentation for ERC review. Since some study participants may receive their primary medical care at a site different from the site where they are enrolled for a study, investigators will need to work with primary medical care providers to obtain and make available all relevant information and documentation for review. As described in the Methods section, our studies have a number of other quality control measures, including a separate reporting form for each event that includes the diagnostic criteria and queries whether the appropriate supporting source documentation has been submitted.

Among the 12 SNA events for which standardized criteria were ultimately developed, 8 represented some form of cardiac or vascular (either arterial or venous)–related events. This reflects the importance of CVD in HIV-infected patients.^{13,14,52–55} In our retrospective ESPRIT review, 236 (42%) reported SNA events were CVD related. Studies have linked the occurrence of CVD events such as myocardial infarction (MI) to specific antiretroviral drugs, as well as to inflammation and endothelial activation, possibly due to uncontrolled HIV replication.^47,48,56 Additionally, lifestyle factors such as smoking, which is more common in HIV-infected persons, may further increase the risk of CVD.⁵⁷ These considerations support collecting information on CVD outcomes in HIV clinical trials, including those evaluating the efficacy and side effects of specific antiretroviral drugs.

“Confirmed” criteria tend to reflect a greater degree of diagnostic certainty and are often based upon more definitive histologic or laboratory procedures. A universal definition of MI has been developed by cardiology experts to serve the needs of epidemiologic surveillance and other research,⁴⁴ and this definition served as the basis for our “confirmed” criteria. For other cardiac events such as CHF, “confirmed” criteria included hemodynamic measurements, ventriculography, echocardiography, or other more definitive diagnostic measures.⁵⁸ For vascular events such as DVT, “confirmed” criteria were based upon contrast venography or other imaging techniques.

Because some sites may diagnose a disease based upon clinical presentation and/or less definitive diagnostic studies, additional case definitions meeting “probable” criteria were developed for many SNA events. For example, “probable” criteria for CHF include a compatible clinical history and abnormal chest X-ray. For an event such as DVT, developing “probable” criteria for patients who might present with relatively nonspecific clinical presentations such as pain and swelling of the lower limb was more challenging.⁵⁹ Advisory bodies have recommended that validated clinical prediction rules be used to estimate pretest probability of DVT.⁶⁰ The Wells prediction rule represents one validated measure^46,60 that was adapted for inclusion in our “probable” criteria.

One challenge in creating standardized event criteria for multisite international studies projected to run over a number of years is that diagnostic standards may evolve, and different sites may utilize different diagnostic studies. As diagnostic technologies are introduced and adopted (such as newer imaging and nucleic acid–based studies), clinical trials may need to incorporate these technological advances into their definitions while at the same time maintaining flexibility in their criteria, especially for resource-limited settings that may lack access to these more expensive or complex technologies. This will require that event criteria have a number of ”confirmed” and “probable” options, to incorporate the diagnostic resources and clinical practice of different study sites. Reporting what specific criteria are being used also allows studies to monitor how different SNA events are being diagnosed and reported.

The START planning committee selected 12 SNA events for which we developed final criteria. The basis for selecting these events included clinical relevance (representing some of the most serious non-AIDS causes of morbidity and mortality), potential association with HIV infection or ART, and prior clinical trial experience (including SMART and ESPRIT) indicating that they could be reliably ascertained. Investigators in other trials may want to include different non-AIDS events or events with lesser degrees of severity. For example, although ESRD was selected as the renal SNA endpoint in START for ERC review, other studies may want to look at chronic renal failure without ESRD. Similarly, although decompensated liver disease was selected as the liver SNA endpoint in START for ERC review, other studies may want to evaluate the occurrence of compensated cirrhosis with greater preservation of hepatic function or may want to categorize in more detail certain specific disease manifestations. Whatever clinical events are selected, we would encourage investigators to have a similar process of using standardized case definitions to reduce investigator bias and allow those evaluating such trials to identify how clinical events were defined.

CONCLUSION

Our experience highlights a number of important issues that must be considered in evaluating SNA events in HIV clinical trials. These include developing objective definitions for “confirmed” and “probable” events, obtaining adequate clinical information and supporting source documentation from participating sites, and having a system for evaluation and validation of reported events by independent reviewers blinded to treatment arm. We present the criteria for 12 SNA events, developed after an iterative process of consultation and discussion, which other studies may wish to use or adapt. Even if studies choose to look at other clinical events or use somewhat different criteria, we believe the overall procedures and approach outlined in this report can be successfully adapted for use in other HIV clinical trials.

APPENDIX

Final Diagnostic Criteria for Serious Non-AIDS Events in START Trial

Acute Myocardial Infarction

1. Rise and/or fall of cardiac biomarkers (preferably troponin), with at least 1 value above the 99th percentile of the upper reference limit (URL)

2. Occurrence of a compatible clinical syndrome, including symptoms (such as chest pain) consistent with myocardial ischemia

3. Electrocardiogram (ECG) changes indicative of new ischemia (new ST-changes or new left bundle branch block [LBBB]), or development of pathological Q waves on the ECG

4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

5. Sudden unexpected cardiac death involving cardiac arrest before biomarkers are obtained or before a time when biomarkers appear, along with (1) new ST-changes or new LBBB, or (2) evidence of fresh thrombus on coronary angiography or at autopsy

6. In patients with percutaneous coronary interventions and normal baseline troponin, increases in troponin of 3 times the 99th percentile of URL

7. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin of 5 times the 99th percentile of URL plus at least 1 of the following: (1) new pathological Q-waves or new LBBB, (2) angiographically documented new graft or native artery occlusion, or (3) imaging evidence of new loss of viable myocardium

8. Pathologic findings of acute myocardial infarction (including AMI demonstrated as the cause of death on autopsy)

9. Development of (1) evolving new Q waves, or (2) evolving ST elevation, preferably based on at least 2 ECGs taken during the same hospital admission

10. In patients with coronary artery bypass grafting and normal baseline troponin, increases in troponin of 5 times the 99th percentile of URL

Confirmed: One of the following 5 criteria: (1) A + (B or C or D); (2) E; (3) F; (4) G; (5) H (adapted from the 2007 universal definition of myocardial infarction⁴⁴)

Probable: B+I or J

Congestive Heart Failure

1. Clinical signs and symptoms compatible with left- or right-sided heart failure (eg, paroxysmal nocturnal dyspnea, rales or S3 on auscultation, jugular venous distention) without an alternative explanation

2. Hemodynamic measurements, radionucleotide ventriculography, echocardiogram, cardiac catheterization, or multiple gated acquisition scan showing a decreased ejection fraction of <45%

3. Echocardiogram, cardiac catheterization, or other studies showing evidence of increased left atrial pressure or right heart failure

4. Elevated levels of brain natriuretic peptide (BNP) or NT-proBNP

5. Chest X-ray or other imaging study showing evidence of congestive heart failure, including cardiac enlargement

6. Documentation of treatment for congestive heart failure

Confirmed: (A+B) or (A+C) or (A+D)

Probable: A+E+F

Coronary Artery Disease Requiring Drug Treatment

A written report in the medical record documenting:

1. Evidence of myocardial ischemia based on either diagnostic imaging studies (such as a stress echocardiogram or thallium scan) or diagnostic changes on a electrocardiogram (such as during stress testing or an episode of chest pain)

2. Evidence of coronary artery disease based on coronary angiography or other diagnostic imaging studies

3. Other evidence of myocardial ischemia and/or coronary artery disease (including that based primarily upon symptoms and clinical presentation)

4. Use of medications given to treat or prevent angina (eg, nitrates, beta blockers, calcium channel blockers)

Confirmed: (A or B) + D

Probable: C + D

Coronary Revascularization

Confirmed: A procedure report, hospital discharge summary, or other medical record from the hospitalization during which the procedure was performed for treatment of coronary artery disease (including coronary artery bypass graft, coronary artery stent implant, coronary artherectomy, and percutaneous transluminal angioplasty), or a consultation note from the participant’s cardiologist documenting the occurrence of the procedure

Probable: Not applicable

Decompensated Liver Disease

1. Histologic, radiographic, or ultrasound evidence of cirrhosis, as documented by 1 of the following:

   1. Histologic evidence of cirrhosis obtained by liver biopsy or autopsy

   2. Magnetic resonance imaging (MRI) or computed tomography (CT) scan consistent with cirrhosis

   3. A positive result on transient elastography (FibroScan) or other ultrasound imaging consistent with cirrhosis

2. Clinical evidence of decompensation, as documented by 1 of the following and without an alternative explanation:

   1. Ascites

   2. Hepatic encephalopathy

   3. Bleeding from gastric or esophageal varices

   4. Spontaneous bacterial peritonitis

Confirmed: A+B

Probable: B

Deep Vein Thrombosis

1. Diagnosis of deep vein thrombosis (DVT) by contrast venography, helical computed tomography, MRI, ultrasonography, or other comparable imaging techniques

2. An elevated D-dimer test or abnormal plethysmography

3. A score on the Wells Clinical Prediction Rule for DVT of ≥3 points

4. Absence of alternative diagnosis as likely or greater than that of DVT

Wells Clinical Prediction Rule for DVT (adapted from Wells PS, et al.⁴⁶)

One point for each of the following:

• Active cancer (treatment ongoing or within previous 6 months, or palliative)

• Paralysis, paresis, or plaster immobilization of lower extremities

• Recently bedridden for more than 3 days, or major surgery, within 4 weeks

• Localized tenderness along distribution of the deep venous system

• Entire leg swollen

• Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured 10 cm below tibial tuberosity)

• Pitting edema (greater in the symptomatic leg)

• Collateral superficial veins (non-varicose)

Confirmed: A

Probable: B+C+D

Diabetes Mellitus

1. Symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dL (11.1 mmol/L) (Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria and polydipsia.)

2. Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L) (Fasting is defined as no caloric intake for at least 8 hours.)

3. 2-hour post-load glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (The test should be performed as described by the World Health Organization, using glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.)

Confirmed: A or B or C

Probable: Not applicable

End-Stage Renal Disease

1. Hemodialysis or peritoneal dialysis documented in a clinical note for a period of at least 3 months

2. A kidney transplant, documented in a clinical note

3. Hemodialysis or peritoneal dialysis documented in a clinical note for a period of at least 1 month and up to the time of death in a patient who dies before 3 months after dialysis begins.

Confirmed: A or B

Probable: C

Non-AIDS–Defining Cancer

1. Diagnosis of cancer other than lymphoma, Kaposi’s sarcoma (KS), or invasive cervical cancer in an autopsy report

2. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a pathology report that established the diagnosis

3. Diagnosis of cancer other than lymphoma, KS, or invasive cervical cancer in a hospital discharge summary or consultation note from the hospitalization or clinic visit during which the diagnosis was established

Confirmed: A or B

Probable: C

Peripheral Arterial Disease

1. Compatible clinical signs and symptoms (eg, intermittent claudication, femoral bruit, decreased peripheral pulses, change in color or temperature of limb suggesting peripheral arterial disease)

2. Positive results on diagnostic imaging studies (eg, Doppler ultrasound, contrast arteriography, MRI arteriography)

3. Ankle Brachial Pressure Index < 0.90 in non-diabetics

4. A procedure report, hospital discharge summary, or other medical record from the hospitalization during which the procedure was performed documenting an invasive procedure for treatment of peripheral arterial disease (eg, percutaneous transluminal angioplasty, endovascular procedures, or vascular surgery), or a consultation note documenting the occurrence of the procedure

Confirmed: (A+B) or (A+C) or D

Probable: A

Pulmonary Embolism

1. Symptoms compatible with pulmonary embolism, such as shortness of breath, chest pain, or hemoptysis

2. Results consistent with a diagnosis of pulmonary embolism on pulmonary angiography, helical CT, ventilation-perfusion scan, or other comparable imaging studies

3. A diagnosis of pulmonary embolism on autopsy

4. Results consistent with a diagnosis of DVT on venography, ultrasound, or other comparable imaging studies

5. A chest X-ray which, if performed, does not suggest an alternative etiology for the symptoms described in criteria A

Confirmed: (A+B) or C

Probable: A+D+E

Stroke

1. Acute onset with a clinically compatible course, including unequivocal objective findings of a localizing neurologic deficit

2. CT or MRI compatible with diagnosis of stroke and current neurologic signs and symptoms

3. Stroke diagnosed as cause of death at autopsy

4. Positive lumbar puncture compatible with subarachnoid hemorrhage

5. Death certificate or death note from medical record listing stroke as cause of death

Confirmed: (A+B) or C

Probable: (A+D) or (A+E)