Simplified approach to investigation of suspected VTE Diagnosis of DVT and PE THSNA 2016, Chicago 15 April 2016 Clive Kearon, McMaster University, Canada
Relevant Disclosures Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Canadian Institutes Health Research Heart & Stroke Foundation of Ontario National Institutes of Health Bayer Inc. No relevant Bayer Inc. No relevant No relevant No relevant No relevant
Outline Goals of diagnostic testing Ruling-in & Rule-out VTE Clinical evaluation as a diagnostic test D-dimer (with clinical evaluation) Imaging tests for DVT and PE Diagnostic combinations Difficult diagnostic situations
Goal of Diagnostic Testing for DVT & PE Who needs treatment have VTE & Anticoagulants will do more good than harm Who doesn t need treatment don t have VTE OR VTE but anticoags more harm than good (will resolve and won t recur without Rx) Need to narrow differential diagnosis
Ruling-in and Ruling-out a Diagnosis What level of certainty is acceptable?
Ruling-in and Ruling-out a Diagnosis What level of certainty is acceptable? Ruling-in (to treat) Depends on toxicity of treatment - high certainty if toxic Ruling-out (not to treat) Depends on consequences of missed diagnosis - high certainty if:(i) rapidly fatal and (ii) effective treatment
Ruling-in DVT or PE Probability of PE ³85% Anticoagulants are toxic (~4% bleeding 3 m) Ruling-out DVT or PE Probability recurrent VTE 2% Recurrent PE may be fatal Anticoagulants are very effective (~ 80% RR)
100% 85% VTE Diagnosed 50% 2% 0% VTE Excluded management
100% 85% PTP prevalence VTE Diagnosed 50% ~25% 2% 0% VTE Excluded management
First diagnostic assessment
Clinical Assessment of DVT & PE Signs and symptoms Risk factor for VTE Alternative diagnosis as likely
Alternative diagnosis as likely -2 Active cancer 1 Paralysis, paresis or plaster cast 1 Bedridden > 3 days (1 month) 1 Tenderness of deep veins 1 Entire leg swollen 1 Calf swelling (3 cm > other leg) 1 Pitting edema 1 Dilated superficial veins 1 History of VTE 1 Total points Clinical Assessment: Low: < 1; Moderate: 1-2; High > 2 for first or recurrent DVT Wells, J Intern Med 1998 Geersing BMJ 2014
No other more likely diagnosis 3 Signs & Symptoms of DVT (tender/swelling) 3 Active cancer 1 Previous DVT or PE 1.5 Immobilization / Surgery <4 weeks 1.5 Heart rate > 100/min 1.5 Hemoptysis 1 Total points Clinical Assessment: Low or Unlikely: < 4.5 for PE Wells, Thromb Haemost 2000 Moderate: 4.5-6; High: > 6
Wells Model for DVT & PE Clinical Suspicion Prevalence VTE High Moderate Low (15% of patients) (35% of patients) (50% of patients) 75% 25% <10%
Wells Model for DVT & PE Clinical Suspicion High Moderate Low Prevalence VTE 75% 25% <10% Likelihood Ratio ~8 ~1 ~0.3
100% 85% PTP Clinical PTP VTE Diagnosed High 50% Moderate Low 2% 0% VTE Excluded management
D-dimer
Cross-linked fibrin Plasmin D-dimer
Almost always increased with acute VTE (sensitive test) Increased by other conditions and age (non-specific test)
D-dimer Very sensitive: very high NPV, rarely negative ( 95%) ( 98%) (~30%) e.g. D-dimer <500 ug FEU/L Mod sensitive: lower NPV, often negative (~90%) (~95%) (~60%) e.g. SimpliRED +ive or ive
100% 85% 50% ~25% PTP prevalence Very Sensitive D-dimer Positive VTE Diagnosed High C-PTP rarely negative lower NPV not worth doing 2% 0% Negative VTE Excluded management
100% 85% PTP prevalence Moderately Sensitive D-dimer Mod Sen D-dimer + PTP 50% ~25% 2% 0% Negative Negative + Low PTP
To get more negative D-dimers
To get more negative D-dimers Increase D-dimer threshold (higher specificity & lower sensitivity) Two ways proposed
Age-adjusted D-dimer threshold Theory: Because D-dimer increases with age, can use higher threshold in elderly 50 years Threshold 500ug/L >50 years Threshold = age x 10 ug/l e.g. 78 years x 10 = 780ug/L
Age-adjusted D-dimer threshold Supported by: Many retrospective analyses for DVT and PE One prospective cohort of suspected PE Non-high C-PTP & D-dimer 500 to Age x 10 Prevalence: 337/3346 (10.1%) VTE at 3 mo: 1/331 (0.3%, 95%CI 0.1 1.7) Righini for ADJUST-PE JAMA 2014
C-PTP-adjusted D-dimer threshold Theory: Because less VTE with low C-PTP, can exclude VTE with much higher D-dimer Low C-PTP Threshold 1,000ug/L Moderate C-PTP Threshold 500ug/L 2-fold difference
C-PTP-adjusted D-dimer threshold Supported by: Some retrospective analyses for DVT and PE One randomized trial in suspected DVT Low C-PTP CPTP & D-dimer 500 to 999 Prevalence in outpatients: 169/1422 (11.9%) VTE at 3 mo: 0/169 (0%, 95%CI 0.0 2.2) RCT comparison: -0.3% (95%CI -1.8 to 0.8) Linkins for SELECT Ann Intern Med 2013
D-dimer not worth doing if: Very unlikely to get a negative result very high C-PTP another reason for a positive test Low NPV will not change management very high C-PTP Eg: After surgery; cancer; sepsis
Okay! When you can t rule out DVT or PE with Clinical PTP & D-dimer?
Diagnostic Imaging for DVT
Compression Ultrasonography (CUS) Imaging Test of Choice for DVT
US probe US probe No compression Compression
Common Femoral Proximal US Whole leg US Calf v. Trifurcation
Proximal US Common Femoral Calf v. Trifurcation easy accurate DVT important often diagnostic with C-PTP or D-d alone, does not exclude all DVT may require 2 nd US after 1 week
Whole leg US Common Femoral Calf v. Trifurcation (with distal veins) more complex less accurate DVT of uncertain importance excludes all DVT Distal US may be an unhelpful additional test
Diagnostic for First DVT US of proximal veins Venography (ascending, CT, MRI) Excludes DVT (including recurrent) Two of: Low C-PTP Negative D-dimer (moderate sensitivity) Negative proximal CUS (or no new vs. pervious) Negative proximal CUS on Day 1 and 7 (serial US) Negative ultrasound of all deep veins Negative D-dimer (very sensitive + non-high C-PTP) Venography of all deep veins
Recurrent DVT: additional criteria (thrombus can persist indefinitely) Diagnostic for Recurrent DVT New DVT on proximal US compared to previous (new CFV, Pop, Tri; 4 mm diam; 10 cm longer) Venography (ascending, CT, direct thrombus imaging MRI) Excludes recurrent DVT No new DVT on serial testing (Day 7, Day 14) No acute findings on venography (ascend, CT, MRI)
Diagnostic Imaging for PE
CT Pulmonary Angiography (CTPA)
No PE on CTPA ( & good quality study [~95%]) Multidetector CT, 12 studies; 2982 patients VTE 3 mo follow-up: 1.1% (95% CI 0.7 1.4) Carrier J Thromb Haemost 2010
Positive Predictive Value of CT by Anatomical Level & Clinical Assessment Clinical Suspicion High Intermed. Low All Main / lobar 96% 99% 89% 97% Segmental 100% 79% 64% 68% Sub-seg. none ~33% ~20% 25%
Positive Predictive Value of CT by Anatomical Level & Clinical Assessment Clinical Suspicion High Intermed. Low All Main / lobar 96% 99% 89% 97% Segmental 100% 79% 64% 68% Sub-seg. none ~33% ~20% 25%
Ventilation-Perfusion Scanning
Ventilation-Perfusion Scanning Often preferred to CTPA Renal impairment Contrast dye allergy Younger (esp. females <40 yr) Pregnancy
Ventilation/Perfusion Scan and Clinical Assessment Normal perfusion ~25% Hi-prob & mod/high PTP ~10% Other combinations ~65% (overall prevalence of PE ~20%) PE - + +
SPECT V/Q scanning (single-photon emission CT) 3 D ventilation and perfusion imaging better resolution of defects than 2D planar non-diagnostic reduced from ~60% to 5% the general impression is that SPECT is better than planar Stein J Nucl Med 2009; SNM practice Guidelines J Nucl Med 2012
SPECT V/Q scanning BUT, NO: Large, prospective, multicentre studies WITH Blind comparison with a criterion standard OR Follow-up after withholding anticoagulation with No PE interpretation
Non-diagnostic combinations DVT Hx VTE, abnormal US, D-dimer +ive (Serial US; may treat) Small abnormality on US, D-dimer +ive (Serial US; may treat) PE Non-diagnostic CTPA (technical, small ILFD, Hx VTE) & no DVT & D-dimer +ive (Serial US; 2 nd CTPA) SPECT non-diagnostic V/Q (no CTPA; renal failure) & no DVT & D-dimer +ive (Serial US;?CTPA)
Conclusions There is no right way to diagnose DVT & PE (many effective strategies) C-PTP and D-dimer can often exclude DVT/PE Can t always reach a definitive diagnosis Can manage safely when can t reach a definitive diagnosis (often serial tests for DVT)