A Novel Technique for Performing Transfemoral Transcatheter Self-Expanding Aortic Valve Replacement With No Contrast Which Minimizes Acute Kidney Injury.

Transcatheter aortic valve replacement (TAVR) treats severe aortic stenosis. However, patients with limited renal function may be ineligible for contrast use during valve deployment. We evaluate TAVR via transfemoral approach using 2-wire technique and no contrast injection. Primary endpoints are acute kidney injury and procedural success. Safety analysis includes mortality, stroke, myocardial infarction, coronary obstruction, and more. Forty-six patients were included; most with preserved ejection fraction. Baseline creatinine was 1.63 ± 0.68 and post-TAVR was significantly better (1.47 ± 0.64, P < 0.01). No statistical difference existed between creatinine at baseline and 30 days. After TAVR, 91% had no paravalvular leak (PVL). Peak-velocity post-TAVR was 1.32 ± 0.33 and mean-gradient was 7 ± 4. No valve repositioning during deployment was required. No mortality at 30 days without incidence of stroke, myocardial infarction or coronary obstruction. One patient had retroperitoneal bleeding requiring transfusion. The noncontrast technique for self-expanding valve deployment is feasible and safe in patients who cannot tolerate contrast.

Diversity in modern heart failure trials: Where are we, and where are we going.

Over the last three decades, increased attention has been given to the representation of historically underrepresented groups within the landscape of pivotal clinical trials. However, recent events (i.e., coronavirus pandemic) have laid bare the potential continuation of historic inequities in available clinical trials and studies aimed at the care of broad patient populations. Anecdotally, cardiovascular disease (CVD) has not been immune to these disparities. Within this review, we examine and discuss recent landmark CVD trials, with a specific focus on the representation of Blacks within several critically foundational heart failure clinical trials tied to contemporary treatment strategies and drug approvals. We also discuss solutions for inequities within the landscape of cardiovascular trials. Building a more diverse clinical trial workforce coupled with intentional efforts to increase clinical trial diversity will advance equity in cardiovascular care.

Contemporary Management of Patent Foramen Ovale: A Multinational Survey on Cardiologists' Perspective.

OBJECTIVES: The purpose of our survey is to analyze the clinical approach used by interventional and imaging cardiologists to diagnose, treat, and follow-up patients with PFO-related left circulation thromboembolism in different parts of the world with particular emphasis on adherence to current guidelines. BACKGROUND: Firm guidelines do not cover many aspects of PFO-related patient care. Consequently, very disparate approaches exist among clinicians in the real-world. METHODS: A 24-item electronic questionnaire was sent directly to experienced cardiology specialists practicing at consultant/attending positions directly involved in PFO closure management in the United States, United Kingdom, Gulf countries, and other countries. There were no unanswered questions. Responses were recorded between October 2019 and July 2020. RESULTS: Seventy-one responses were obtained: 31 from the UK, 19 from the US, 16 from Gulf countries, 2 from Poland, and 1 response from Australia, Italy, and Switzerland. The overall response rate was 76%. Significant differences between regions were noted in the duration of ECG monitoring during the diagnostic process, PFO closure for left circulation thromboembolism other than stroke/transient ischemic attack, and intraoperative use of intracardiac echocardiography. A similar pattern was noted in the lack of routine screening for thrombophilia and the use of the long-term single antiplatelet therapy. CONCLUSIONS: The study shows a vast spectrum of opinions on the optimal approach to PFO closure with significant differences between the US, UK, and Gulf countries. The results stress the need for systematic, high-quality data on the diagnostic work-up and follow-up strategies to inform the standardized approach.

Outcomes following endovascular therapy for acute stroke by interventional cardiologists.

OBJECTIVES: To summarize the outcomes of acute ischemic stroke (AIS) intervention by interventional cardiologists (IC) working on a stroke team. BACKGROUND: There is a geographic maldistribution of dedicated neuro-interventionalists (NI) to treat large vessel occlusion (LVO) AIS. METHODS: Results of 166 consecutive patients who received endovascular therapy (EVT) for AIS due to LVO by IC at three centers between 2009 and 2019 are reported. A modified Rankin score (mRs) of ≤ 2 at 90 days after EVT was used as the primary measurement of a good neurological outcome. Univariate logistic regression was used to evaluate predictors of the mRS > 2 and mortality. Those variables with significance of p < .2 from the univariate analysis were included in a multivariate analysis. RESULTS: All-cause mortality at 30 days was 22%. A favorable clinical outcome, mRS ≤ 2 at 90 days, was 49%. After multivariate analysis and controlling for confounders, a higher baseline NIHSS was predictive of 30-day mortality (OR 1.20 [95% CI 1.09-1.32] p < .001) and unfavorable clinical outcome (mRS > 2) at 90 days (OR 1.16 [95% CI 1.07-1.25] p < .001). CONCLUSION: Outcomes for carotid stent capable IC performing EVT for AIS are comparable to those achieved by NI physicians in major randomized clinical trials. Our data supports conducting a clinical trial of carotid stent capable IC working on multidisciplinary stroke teams to perform EVT for AIS due to LVO in communities and hospitals without timely access (<60 min by ground transport) to dedicated NI.

Renal denervation: Alternative treatment options for hypertension?

Hypertension affects millions of Americans and has adverse long-term consequences increasing morbidity and mortality. Resistant hypertension (RH) continues to be difficult to treat with medications alone which may be associated with significant side effects. Alternate therapies have been evaluated for treating RH and renal denervation has been investigated extensively. We review the data from renal denervation trials and other novel technologies which are not FDA approved to date.

Renal revascularization in resistant hypertension.

Renal artery stenosis (RAS) is a common cause of secondary hypertension (HTN) and may lead to resistant (refractory) HTN despite guideline directed medical therapy. Although randomized controlled trials comparing medical therapy to medical therapy and renal artery stenting have shown no benefit with renal artery stenting, according to comparative effectiveness reviews by the Agency for Healthcare Research and Quality, the trials did not enroll patients with the most severe RAS who would be more likely to benefit from renal stenting. Because of limitations of conventional angiography, it is important to assess the hemodynamic severity of moderate (50%-70%) RAS lesions with a hemodynamic measurement. We review techniques to optimize patient selection, to minimize procedural complications, and to facilitate durable patency of renal stenting. We also review the current ACC/AHA Guidelines and SCAI Appropriate Use Criteria as they relate to renal stenting.

When and How Should We Revascularize Patients With Atherosclerotic Renal Artery Stenosis?

Atherosclerotic renal artery stenosis is the leading cause of secondary hypertension and may lead to resistant (refractory) hypertension, progressive decline in renal function, and cardiac destabilization syndromes (pulmonary edema, recurrent heart failure, or acute coronary syndromes) despite guideline-directed medical therapy. Although randomized controlled trials comparing medical therapy with medical therapy and renal artery stenting have failed to show a benefit for renal artery stenting, according to comparative effectiveness reviews by the Agency for Healthcare Research and Quality, the trials may not have enrolled patients with the most severe atherosclerotic renal artery stenosis, who would be more likely to benefit from renal stenting. Because of limitations of conventional angiography, it is critical that the hemodynamic severity of moderately severe (50% to 70%) atherosclerotic renal artery stenosis lesions be confirmed on hemodynamic measurement. The authors review techniques to optimize patient selection, to minimize procedural complications, and to facilitate durable patency of renal stenting. The authors also review the current American College of Cardiology and American Heart Association guidelines and the Society for Cardiovascular Angiography and Interventions appropriate use criteria as they relate to renal stenting.

Eligibility for alirocumab or evolocumab treatment in 1090 hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥70 mg/dL despite maximal-tolerated LDL-cholesterol-lowering therapy.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors, Praluent (alirocumab [ALI]) and Repatha (evolocumab [EVO]) have been approved as adjuncts to the standard-of-care maximal-tolerated dose (MTD) of low-density lipoprotein cholesterol (LDLC)-lowering therapy (LLT), statin therapy, in heterozygous (HeFH) (ALI or EVO) or homozygous (EVO) familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient (both). Since LDLC lowering has been revolutionized by ALI and EVO, specialty pharmaceutical pricing models will be applied to a mass market. METHODS: We applied US Food and Drug Administration (FDA) and insurance eligibility criteria for ALI and EVO to 1090 hypercholesterolemic patients serially referred over 3 years who then received ≥2 months maximal-tolerated dose of standard-of-care LDL cholesterol-lowering therapy (MTDLLT) with follow-up LDLC ≥70 mg/dL. MTDLLT did not include ALI or EVO, which had not been commercially approved before completion of this study. RESULTS: Of the 1090 patients, 140 (13%) had HeFH by clinical diagnostic criteria and/or CVD with LDLC >100 mg/dL despite ≥2 months on MTDLLT, meeting FDA insurance criteria for ALI or EVO therapy. Another 51 (5%) patients were statin intolerant, without HeFH or CVD. CONCLUSION: If 13% of patients with HeFH-CVD and LDLC >100 mg/dL despite MTDLLT are eligible for ALI or EVO, then specialty pharmaceutical pricing models (~$14,300/year) might be used in an estimated 10 million HeFH-CVD patients. Whether the health care savings arising from the anticipated reduction of CVD events by ALI or EVO justify their costs in populations with HeFH-CVD and LDLC >100 mg/dL despite MTDLLT remains to be determined.

Progressively Worsening Premature Coronary Artery Disease: Adding Anticoagulation Stabilizes-Reverses Clinical Symptomatic Disease Progression in Thrombophilic-Atherothrombotic Patients: A Pilot Study.

In 35 patients with 116 severe premature cardiovascular disease (CVD) events (median age: 48 years), 14 having worsening CVD despite maximal intervention, we evaluated thrombophilia and speculated that anticoagulation might arrest-reverse progressive thrombophilic-atherothrombotic CVD. Thrombophilia-hypofibrinolysis in the 35 patients was compared to 110 patients with venous thromboembolism (VTE) without CVD and to 110 healthy normal controls. Efficacy-safety of anticoagulation was prospectively assessed in 14 of the 35 patients whose CVD worsened over 2 years despite maximal medical-surgical intervention. At entry on maximally tolerated lipid-lowering therapy, median low-density lipoprotein was 88 mg/dL. Measures of thrombophilia-hypofibrinolysis in the 35 cases differed from 110 VTE controls only for the lupus anticoagulant, present in 6 (21%) of 28 cases versus 4 (4%) of 91 VTE controls ( P = .01), and for high anticardiolipin antibodies (ACLAs) immunoglobulin G, 5 (14%) of 35 cases versus 4 of 108 VTE controls (4%), P = .04. The 14 patients who were anticoagulated differed from 110 VTE controls only for the lupus anticoagulant, 38% versus 4%, P = .001, and for high lipoprotein (a), 46% versus 17%, P = .028, respectively. The 14 patients with atherothrombosis having inexorably worsening CAD despite maximal medical-surgical therapy were anticoagulated for 6.5 years (median), with clinical CVD progression arrested in 12 (86%), and all 12 became asymptomatic. In the 35 patients with premature CVD, thrombophilia was pervasive, comparable to or more severe than in VTE controls without CVD. When CVD progressively worsens despite maximal intervention, thrombophilia and atherosclerosis (atherothrombosis) are commonly concurrent, and the downhill course of CVD may be arrested-stabilized by anticoagulation.

Associations between Serum 25-hydroxyvitamin D and Lipids, Lipoprotein Cholesterols, and Homocysteine.

BACKGROUND: Serum 25(OH) vitamin D levels are inversely associated with cardiovascular disease (CVD) mortality, mediated in part by independent positive relationships with high-density lipoprotein cholesterol (HDLC) and inverse relationships with low-density lipoprotein cholesterol (LDLC), triglyceride, and homocysteine. AIMS: In this study, we assessed relationships between fasting serum vitamin D and lipids, lipoprotein cholesterols, and homocysteine. MATERIALS AND METHODS: We studied 1534 patients sequentially referred to our center from 2007 to 2016. Fasting serum total 25(OH) vitamin D, plasma cholesterol, triglyceride, HDLC, LDLC, and homocysteine were measured. Stepwise regression models were used with total cholesterol, triglyceride, HDLC, LDLC, and homocysteine as dependent variables and explanatory variables age, race, gender, body mass index (BMI), and serum vitamin D levels. Relationships between quintiles of serum vitamin D and triglycerides, HDLC, LDLC, and homocysteine were assessed after covariance adjusting for age, race, gender, and BMI. RESULTS: Fasting serum vitamin D was positively correlated with age, HDLC, and White race, and was inversely correlated with BMI, total and LDL cholesterol, triglyceride, and fasting serum homocysteine (P ≤ 0.0001 for all). Serum vitamin D was a significant independent inverse explanatory variable for total cholesterol, triglyceride, and LDL cholesterol, and accounted for the largest amount of variance in serum total cholesterol (partial R (2) =3.6%), triglyceride (partial R (2) =3.1%), and LDLC (partial R (2) =2.9%) (P < 0.0001 for all). Serum vitamin D was a significant positive explanatory variable for HDLC (partial R (2) = 1.4%, P < 0.0001), and a significant inverse explanatory variable for homocysteine (partial R (2) = 6.0-12.6%). CONCLUSIONS: In hyperlipidemic patients, serum vitamin D was a significant independent inverse determinant of total cholesterol, LDLC, triglyceride, and homocysteine, and a significant independent positive determinant of HDLC. Thus, serum vitamin D might be protective against CVD.

Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant.

BACKGROUND: When exogenous testosterone or treatments to elevate testosterone (human chorionic gonadotropin [HCG] or Clomid) are prescribed for men who have antecedent thrombophilia, deep venous thrombosis and pulmonary embolism often occur and may recur despite adequate anticoagulation if testosterone therapy is continued. CASE PRESENTATION: A 55-year-old white male was referred to us because of 4 thrombotic events, 3 despite adequate anticoagulation over a 5-year period. We assessed interactions between thrombophilia, exogenous testosterone therapy, and recurrent thrombosis. In 2009, despite low-normal serum testosterone 334 ng/dL (lower normal limit [LNL] 300 ng/dL), he was given testosterone (TT) cypionate (50 mg/week) and human chorionic gonadotropin (HCG; 500 units/week) for presumed hypogonadism. Ten months later, with supranormal serum T (1385 ng/dL, upper normal limit [UNL] 827 ng/dL) and estradiol (E2) 45 pg/mL (UNL 41 pg/mL), he had a pulmonary embolus (PE) and was then anticoagulated for 2 years (enoxaparin, then warfarin). Four years later, on TT-HCG, he had his first deep venous thrombosis (DVT). TT was stopped and HCG continued; he was anticoagulated (enoxaparin, then warfarin, then apixaban, then fondaparinux). One year after his first DVT, on HCG, still on fondaparinux, he had a second DVT (5/315), was anticoagulated (enoxaparin + warfarin), with a Greenfield filter placed, but 8 days later had a second PE. Thrombophilia testing revealed the lupus anticoagulant. After stopping HCG, and maintained on warfarin, he has been free of further DVT-PE for 9 months. CONCLUSION: When DVT-PE occur on TT or HCG, in the presence of thrombophilia, TT-HCG should be stopped, lest DVT-PE reoccur despite concurrent anticoagulation.

Safety of 50,000-100,000 Units of Vitamin D3/Week in Vitamin D-Deficient, Hypercholesterolemic Patients with Reversible Statin Intolerance.

BACKGROUND: Vitamin D deficiency (<32 ng/mL) is a reversible cause of statin-intolerance, usually requiring vitamin D3 (50,000-100,000 IU/week) to normalize serum D, allowing reinstitution of statins. Longitudinal safety assessment of serum vitamin D, calcium, and estimated glomerular filtration rate (eGFR) is important. AIMS: Prospectively assess the safety-efficacy of vitamin D3 therapy. MATERIALS AND METHODS: In 282 statin-intolerant hypercholesterolemic patients for 6 months and in 112 of the 282 patients for 12 months, with low-entry serum vitamin D (<32 ng/mL), we assessed safety-efficacy of vitamin D3 therapy (50,000-100,000 IU/week). RESULTS: On mean (66,600 IU) and median (50,000 IU) of vitamin D3/week in 282 patients at 6 months, serum vitamin D rose from pretreatment (21-median) to 46 ng/mL (P < 0.0001), and became high (>100 ng/mL) but not toxic (>150 ng/mL) in 4 patients (1.4%). Median serum calcium was unchanged from entry (9.60 mg/dL) to 9.60 at 6 months (P = .36), with no trend of change (P = .16). Median eGFR was unchanged from entry (84 mL/min/1.73) to 83 at 6 months (P = .57), with no trend of change (P = .59). On vitamin D3 71,700 (mean) and 50,000 IU/week (median) at 12 months in 112 patients, serum vitamin D rose from pretreatment (21-median) to 51 ng/mL (P < 0.0001), and became high (>100 but <150 ng/mL) in 1 (0.9%) at 12 months. Median serum calcium was unchanged from entry (9.60 mg/dL) to 9.60 mg/dL and 9.60 mg/dL at 6 months and 12 months, respectively; P > 0.3. eGFR did not change from 79 mL/min/1.73 at entry to 74 mL/min/1.73 and 77 mL/min/1.73 at 6 months and 12 months, P > 0.3. There was no trend in the change in serum calcium (P > 0.5 for 6 months and 12 months), and no change of eGFR for 6 months and 12 months, P > 0.15. CONCLUSIONS: Vitamin D3 therapy (50,000-100,000 IU/week) was safe and effective when given for 12 months to reverse statin intolerance in patients with vitamin D deficiency. Serum vitamin D rarely exceeded 100 ng/mL, never reached toxic levels, and there were no significant change in serum calcium or eGFR.

Hospitalization for pulmonary embolism associated with antecedent testosterone or estrogen therapy in patients found to have familial and acquired thrombophilia.

BACKGROUND: In patients hospitalized over a 4 year period for pulmonary embolism (PE), we assessed relationships of testosterone (TT) and estrogen therapy (ET) anteceding PE in patients found to have familial-acquired thrombophilia. METHODS: From 2011 through 2014, 347 patients were hospitalized in Cincinnati Mercy Hospitals with PE. Retrospective chart review was used to identify patients receiving TT or ET before PE; coagulation studies were done prospectively if necessary. RESULTS: Preceding hospitalization for PE, 8 of 154 men (5 %) used TT, and 24 of 193 women (12 %) used ET. The median number of months from the initiation of TT or ET to development of PE was 7 months in men and 18 months in women. Of the 6 men having coagulation measures, all had ≥ 1 thrombophilia, and of the 18 women having measures of coagulation, 16 had ≥ 1 thrombophilia. The sensitivity of a previous history of thrombosis to predict PE was low, 25 % (2/8 men), 4 % (1/24 women). CONCLUSIONS: Of 154 men hospitalized for PE, 8 (5 %) used TT, and of 193 women, 24 (12 %) used ET. Our data suggests that PE is an important complication of TT in men and ET in women, in part reflecting an interaction between familial and acquired thrombophilia and exogenous hormone use.

Eligibility for PCSK9 treatment in 734 Hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥ 70 mg/dl despite maximal tolerated cholesterol lowering therapy.

BACKGROUND: LDL cholesterol (LDLC) lowering has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha), approved as adjuncts to maximally tolerated cholesterol lowering therapy in heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, and/or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient. METHODS: We applied FDA and insurance eligibility criteria for PCSK9 inhibitor use in 734 hypercholesterolemic patients serially referred over 3 years who then received ≥ 2 months maximally tolerated LDLC lowering therapy with follow up LDLC ≥ 70 mg/dl, and in 50 patients approved by insurance for PCSK9 inhibitors. We documented the percentage of patients with HeFH and/or CVD who met FDA and insurance criteria for PCSK9 inhibitor therapy using LDLC goal-based guidelines. RESULTS: Of 734 patients with LDLC ≥ 70 mg/dl after ≥ 2 months maximally tolerated LDLC lowering therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy. Another 66 (9%) patients were statin intolerant, without HeFH or CVD. Of the 50 patients whose PCSK9 inhibitor therapy was approved for insurance coverage, 45 (90%) had LDLC > 100 mg/dl after ≥ 2 months on maximally tolerated LDLC lowering therapy. Seventeen of these 50 patients (34%) had HeFH without CVD (LDLC on treatment 180 ± 50 mg/dl), 15 (30%) had CVD without HeFH (LDLC on treatment 124 ± 26 mg/dl), 14 (28%) had both HeFH and CVD (LDLC on treatment 190 ± 53 mg/dl), and 4 (8%) had neither HeFH nor CVD (LCLC 142 ± 11 mg/dl). CONCLUSION: Of 734 patients referred for LDLC reduction, with LDLC ≥ 70 mg/dl after ≥ 2 months on maximally tolerated therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy as an adjunct to diet-maximally tolerated cholesterol lowering therapy in HeFH or CVD. If 30% of patients with high LDLC and HeFH-CVD are eligible for PCSK9 inhibitors, then specialty pharmaceutical pricing models (~$14,300/year) will collide with tens of millions of HeFH-CVD patients. We speculate that if there was a 50 % reduction in CVD, then there would be savings of $245 billion, in the middle of the range of estimated PCSK9 inhibitor costs of $185-342 billion. Whether the health care savings arising from the anticipated reduction of CVD events by PCSK9 inhibitors justify their extraordinary costs in broad population use remains to be determined.

Thrombophilia in 67 Patients With Thrombotic Events After Starting Testosterone Therapy.

We compared thrombophilia in 67 cases (59 men and 8 women) with thrombotic events after starting testosterone therapy (TT) versus 111 patient controls having unprovoked venous thrombotic events without TT. In the 67 patients, thrombosis (47 deep venous thrombosis-pulmonary embolism, 16 osteonecrosis, and 4 ocular thrombosis) occurred 6 months (median) after starting TT. Cases differed from controls for factor V Leiden heterozygosity (16 of the 67 [24%] vs 13 [12%] of the 111, P = .038) and for lupus anticoagulant (9 [14%] of the 64 vs 4 [4%] of the 106, P = .019). After a first thrombotic event and continuing TT, 11 cases had a second thrombotic event, despite adequate anticoagulation, 6 of whom, still anticoagulated, had a third thrombosis. Screening for thrombophilia before starting TT should identify men and women at high risk for thrombotic events with an adverse risk-benefit ratio for TT. When TT is given to patients with familial and acquired thrombophilia, thrombosis may occur and recur in thrombophilic men despite anticoagulation.

Testosterone Therapy Can Interact With Thrombophilia, Leading to Osteonecrosis.

Although this effect is not widely recognized, testosterone therapy can interact with thrombophilia, causing osteonecrosis. In 12 men and 4 women who had idiopathic osteonecrosis a median of 6 months after the onset of testosterone therapy, the authors examined the interaction between testosterone therapy and previously undiagnosed thrombophilia. The authors hypothesized that patients who had osteonecrosis after starting testosterone therapy were more likely than 110 normal control subjects or 48 patients who had osteonecrosis and were not receiving testosterone therapy to have thrombophilia. Measures of thrombophilia included Factor V Leiden, prothrombin, PAI-1 gene mutations, Factor VIII, Factor XI, anticardiolipin antibody immunoglobulin G or immunoglobulin M, and homocysteine values. In 10 cases, osteonecrosis occurred 6 months or less after the onset of testosterone therapy, and in all 16 cases, it occurred after a median of 6 months of testosterone therapy. Of the 16 cases, 5 (31%) were Factor V Leiden heterozygotes vs 2 of 109 (2%) healthy control subjects (P=.0003) and 4 of 48 patients who had osteonecrosis and were not receiving testosterone therapy (P=.04). Of the 16 cases, 4 (25%) had high (>150%) Factor VIII levels vs 7 of 103 (7%) healthy control subjects (P=.04), and 3 (19%) had high (>150%) Factor XI levels vs 3 of 101 (3%) healthy control subjects (P=.03). Of the 16 patients with osteonecrosis, 14 (88%) had at least 1 abnormal procoagulant value (of the 8 measured) vs 47 of 110 (43%) healthy control subjects (P=.0009). Of the 5 men whose serum estradiol level was measured while they were receiving testosterone therapy, this level was high (≥42.6 pg/mL) in 4. When testosterone therapy is given to patients with thrombophilia, they are at increased risk for osteonecrosis.

Testosterone, thrombophilia, thrombosis.

We screened previously undiagnosed thrombophilia (V Leiden-prothrombin mutations, Factors VIII and XI, homocysteine, and antiphospholipid antibody [APL] syndrome) in 15 men and 2 women with venous thromboembolism (VTE) or osteonecrosis 7 months (median) after starting testosterone therapy (TT), gel (30-50 mg/d), intramuscular (100-400 mg/wk), or human chorionic gonadotropin (HCG) (6000 IU/wk). Thrombophilia was studied in 2 healthy control groups without thrombosis (97 normal controls, 31 subjects on TT) and in a third control group (n = 22) with VTE, not on TT. Of the 17 cases, 76% had ≥1 thrombophilia vs 19% of 97 normal controls (P < 0.0001), vs 29% of 31 TT controls (P = 0.002). Cases differed from normal controls by Factor V Leiden (12% vs 0%, P = 0.021), by high Factor VIII (>150%) (24% vs 7%, P = 0.058), by high homocysteine (29% vs 5%, P = 0.007), and from both normal and TT controls for APL syndrome (18% vs 2%, P = 0.023, vs 0%, P = 0.04). Despite adequate anticoagulation with TT continued after the first deep venous thrombosis-pulmonary embolus (DVT-PE), 1 man sustained 3 DVT-PEs 5, 8, and 11 months later and a second man had 2 DVT-PEs 1 and 2 months later. Of the 10 cases with serum T measured on TT, 6 (60%) had supranormal T (>800 ng/dL) and of 9 with estradiol measured on TT, 7 (78%) had supranormal levels (>42.6 pg/mL). TT interacts with thrombophilia leading to thrombosis. TT continuation in thrombophilic men is contraindicated because of recurrent thrombi despite anticoagulation. Screening for thrombophilia before starting TT should identify subjects at high risk for VTE with an adverse the risk to benefit ratio for TT.