Week 10 – CLOT

“Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer”

by the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators

N Engl J Med. 2003 Jul 10;349(2):146-53. [free full text]

Malignancy is a pro-thrombotic state, and patients with cancer are at significant and sustained risk of venous thromboembolism (VTE) even when treated with warfarin. Warfarin is a suboptimal drug that requires careful monitoring, and its effective administration is challenging in the setting of cancer-associated difficulties with oral intake, end-organ dysfunction, and drug interactions. The 2003 CLOT trial was designed to evaluate whether treatment with low-molecular-weight heparin (LMWH) was superior to treatment with a vitamin K antagonist (VKA) in the prevention of recurrent VTE.

The study randomized adults with active cancer and newly diagnosed symptomatic DVT or PE to treatment with either dalteparin subQ daily (200 IU/kg daily x1 month, then 150 IU/kg daily x5 months) or a vitamin K antagonist x6 months (target INR 2.5, with 5-7 day LMWH bridge). The primary outcome was the recurrence of symptomatic DVT or PE within 6 months of follow-up. Secondary outcomes included major bleed, any bleeding, and all-cause mortality.

338 patients were randomized to the LMWH group, and 338 were randomized to the VKA group. Baseline characteristics were similar among the two groups. 90% of patients had solid malignancies, and 67% of patients had metastatic disease. Within the VKA group, INR was estimated to be therapeutic 46% of the time, subtherapeutic 30% of the time, and supratherapeutic 24% of the time. Within the six-month follow-up period, symptomatic VTE occurred in 8.0% of the dalteparin group and 15.8% of the VKA group (HR 0.48, 95% CI 0.30-0.77, p=0.002; NNT = 12.9). The Kaplan-Meier estimate of recurrent VTE at 6 months was 9% in the dalteparin group and 17% in the VKA group. 6% of the dalteparin group developed major bleeding versus 6% of the VKA group (p = 0.27). 14% of the dalteparin group sustained any type of bleeding event versus 19% of the VKA group (p = 0.09). Mortality at 6 months was 39% in the dalteparin group versus 41% in the VKA group (p = 0.53).

In summary, treatment of VTE in cancer patients with low-molecular-weight heparin reduced the incidence of recurrent VTE relative to the incidence following treatment with vitamin K antagonists. Notably, this reduction in VTE recurrence was not associated with a change in bleeding risk. However, it also did not correlate with a mortality benefit either. This trial initiated a paradigm shift in the treatment of VTE in cancer. LMWH became the standard of care, although cost and convenience may have limited access and adherence to this treatment.

Until recently, no trial had directly compared a DOAC to LMWH in the prevention of recurrent VTE in malignancy. In an open-label, noninferiority trial, the Hokusai VTE Cancer Investigators demonstrated that the oral Xa inhibitor edoxaban (Savaysa) was noninferior to dalteparin with respect to a composite outcome of recurrent VTE or major bleeding. The 2018 SELECT-D trial compared rivaroxaban (Xarelto) to dalteparin and demonstrated a reduced rate of recurrence among patients treated with rivaroxaban (cumulative 6-month event rate of 4% versus 11%, HR 0.43, 95% CI 0.19–0.99) with no difference in rates of major bleeding but increased “clinically relevant nonmajor bleeding” within the rivaroxaban group.

Further Reading/References:
1. CLOT @ Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Treatment of venous thromboembolism in patients with malignancy”
4. Hokusai VTE Cancer Trial @ Wiki Journal Club
5. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism,” NEJM 2017
6. “Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D).” J Clin Oncol 2018.

Summary by Duncan F. Moore, MD

Image Credit: By Westgate EJ, FitzGerald GA, CC BY 2.5via Wikimedia Commons

Week 52 – EINSTEIN-PE

“Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism”

by the EINSTEIN-PE Investigators

N Engl J Med. 2012 Apr 5;366(14):1287-97. [free full text]

Prior to the introduction of DOACs, the standard of care for treatment of acute VTE was treatment with a vitamin K antagonist (VKA, e.g. warfarin) bridged with LMWH. In 2010, the EINSTEIN-DVT study demonstrated the non-inferiority of rivaroxaban (Xarelto) versus VKA with an enoxaparin bridge in patients with acute DVT in the prevention of recurrent VTE. Subsequently, in this 2012 study, EINSTEIN-PE, the EINSTEIN investigators examined the potential role for rivaroxaban in the treatment of acute PE.

This open-label RCT compared treatment of acute PE (± DVT) with rivaroxaban (15mg PO BID x21 days, followed by 20mg PO daily) versus VKA with an enoxaparin 1mg/kg bridge until the INR was therapeutic for 2+ days and the patient had received at least 5 days of enoxaparin. Patients with cancer were not excluded if they had a life expectancy of ≥ 3 months, but they comprised only ~4.5% of the patient population. Treatment duration was determined by the discretion of the treating physician and was decided prior to randomization. Duration was also a stratifying factor in the randomization. The primary outcome was symptomatic recurrent VTE (fatal or nonfatal). The pre-specified noninferiority margin was 2.0 for the upper limit of the 95% confidence interval of the hazard ratio. The primary safety outcome was “clinically relevant bleeding.”

4833 patients were randomized. In the conventional-therapy group, the INR was in the therapeutic range 62.7% of the time. Symptomatic recurrent VTE occurred in 2.1% of patients in the rivaroxaban group and 1.8% of patients in the conventional-therapy group (HR 1.12, 95% CI 0.75–1.68, p = 0.003 for noninferiority). The p value for superiority of conventional therapy over rivaroxaban was 0.57. A first episode of “clinically relevant bleeding” occurred in 10.3% of the rivaroxaban group versus 11.4% of the conventional-therapy group (HR 0.90, 95% CI 0.76-1.07, p = 0.23).

In a large, open-label RCT, rivaroxaban was shown to be noninferior to standard therapy with a VKA + enoxaparin bridge in the treatment of acute PE. This was the first major RCT to demonstrate the safety and efficacy of a DOAC in the treatment of PE and led to FDA approval of rivaroxaban for the treatment of PE that same year. The following year, the AMPLIFY trial demonstrated that apixaban was noninferior to VKA + LMWH bridge in the prevention of recurrent VTE, and apixaban was also approved by the FDA for the treatment of PE. The 2016 Chest guidelines for Antithrombotic Therapy for VTE Disease recommend the DOACs rivaroxaban, apixaban, dabigatran, or edoxaban over VKA therapy in VTE not associated with cancer. In cancer-associated VTE, LMWH remains the recommended agent. (See the Week 25 – CLOT post.) As noted previously, a study earlier this year in NEJM demonstrated the noninferiority of edoxaban over LMWH in the treatment of cancer-associated VTE.

Further Reading/References:
1. EINSTEIN-DVT @ NEJM
2. EINSTEIN-PE @ Wiki Journal Club
3. EINSTEIN-PE @ 2 Minute Medicine
4. AMPLIFY @ Wiki Journal Club
5. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism” NEJM 2018

Summary by Duncan F. Moore, MD

Week 25 – CLOT

“Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer”

by the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators

N Engl J Med. 2003 Jul 10;349(2):146-53. [free full text]

Malignancy is a pro-thrombotic state, and patients with cancer are at significant and sustained risk of venous thromboembolism (VTE) even when treated with warfarin. Warfarin is a suboptimal drug that requires careful monitoring, and its effective administration is challenging in the setting of cancer-associated difficulties with oral intake, end-organ dysfunction, and drug interactions. The 2003 CLOT trial was designed to evaluate whether treatment with low-molecular-weight heparin (LMWH) was superior to a vitamin K antagonist (VKA) in the prevention of recurrent VTE.

Population: adults with active cancer and newly diagnosed symptomatic DVT or PE

The cancer must have been diagnosed or treated within past 6 months, or the patient must have recurrent or metastatic disease.

Intervention: dalteparin subQ daily (200 IU/kg daily x1 month, then 150 IU/kg daily x5 months)

Comparison: vitamin K antagonist x6 months (with 5-7 day LMWH bridge), target INR 2.5

Outcomes:

primary = recurrence of symptomatic DVT or PE within 6 months follow-up

secondary = major bleeding, any bleeding, all-cause mortality

 

Results:
338 patients were randomized to the LMWH group, and 338 were randomized to the VKA group. Baseline characteristics were similar among the two groups. 90% of patients had solid malignancies, and 67% of patients had metastatic disease. Within the VKA group, INR was estimated to be therapeutic 46% of the time, subtherapeutic 30% of the time, and supratherapeutic 24% of the time.

Within the six-month follow-up period, symptomatic VTE occurred in 8.0% of the dalteparin group and 15.8% of the VKA group (HR 0.48, 95% CI 0.30-0.77, p=0.002; NNT = 12.9). The Kaplan-Meier estimate of recurrent VTE at 6 months was 9% in the dalteparin group and 17% in the VKA group.

6% of the dalteparin group developed major bleeding versus 6% of the VKA group (p = 0.27). 14% of the dalteparin group sustained any type of bleeding event versus 19% of the VKA group (p = 0.09). Mortality at 6 months was 39% in the dalteparin group versus 41% in the VKA group (p = 0.53).

Implication/Discussion:
Treatment of VTE in cancer patients with low-molecular-weight heparin reduced the incidence of recurrent VTE relative to the incidence following treatment with vitamin K antagonists.

Notably, this reduction in VTE recurrence was not associated with a change in bleeding risk. However, it also did not correlate with a mortality benefit either.

This trial initiated a paradigm shift in the treatment of VTE in cancer. LMWH became the standard of care, although access and adherence to this treatment was thought to be limited by cost and convenience.

Until last week, no trial had directly compared a DOAC to LMWH in the prevention of recurrent VTE in malignancy. In an open-label, noninferiority trial, the Hokusai VTE Cancer Investigators demonstrated that the oral Xa inhibitor edoxaban (Savaysa) was noninferior to dalteparin with respect to a composite outcome of recurrent VTE or major bleeding.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Treatment of venous thromboembolism in patients with malignancy”
4. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism,” NEJM 2017

Summary by Duncan F. Moore, MD

Week 15 – TRICC

“A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care”

N Engl J Med. 1999 Feb 11; 340(6): 409-417. [free full text]

Although intuitively a hemoglobin closer to normal physiologic concentration seems like it would be beneficial, the vast majority of the time in inpatient settings we use a hemoglobin concentration of >7g/dL as our threshold for transfusion in anemia. Historically, higher hemoglobin cutoffs were used, often aiming to keep Hgb >10g/dL. In 1999, the landmark TRICC trial was published showing no mortality benefit in the liberal transfusion strategy and even harm in certain subgroup analysis.

Population:

Inclusion: critically ill patients expected to be in ICU > 24h, Hgb ≤ 9g/dL within 72hr of ICU admission, and clinically euvolemic after fluid resuscitation

Exclusion criteria: age < 16, inability to receive blood products, active bleed, chronic anemia, pregnancy, brain death, consideration of withdrawal of care, and admission after routine cardiac procedure.

Intervention: liberal strategy (transfuse to Hgb goal 10-12g/dL, N=420)

Comparison: restrictive strategy (transfuse to Hgb goal 7-9g/dL, N=418)

Primary outcome: 30-day all-cause mortality

Secondary outcomes: 60-day all-cause mortality, mortality during hospital stay (ICU plus step-down), multiple-organ dysfunction score, change in organ dysfunction from baseline

Subgroup analyses: patients with APACHE II score ≤ 20 (i.e. less-ill patients), patients younger than 55, cardiac disease, severe infection/septic shock, and trauma

Results:
The primary outcome of 30-day mortality was similar between the two groups (18.7% vs. 23.3%, p = 0.11). Secondary outcomes of mortality rates during hospitalization were lower in the restrictive strategy (22.2% vs. 28.1%, p = 0.05). 60-day all-cause mortality trended towards lower in the restrictive strategy although did not reach statistical significance (22.7% vs. 26.5 %, p = 0.23). Between the two groups there was no significant difference in multiple-organ dysfunction score or change in organ dysfunction from baseline.

Subgroup analysis was most notable for finding statistically significant benefits for the restrictive strategy in the patients with APACHE II score ≤ 20 and patients younger than 55. In these patients, a restrictive strategy showed decrease in 30-day mortality and a lower multiple-organ dysfunction score. In the subgroups of primary disease process (i.e. cardiac disease, severe infection/septic shock, and trauma) there was no significant difference.

Complications in the ICU were monitored, and there was a significant increase in cardiac events (primarily pulmonary edema) in the liberal strategy compared to the restrictive strategy.

Discussion/Implication:
TRICC showed no difference in 30-day mortality between a restrictive and liberal transfusion strategy. Secondary outcomes were notable for a decrease in inpatient mortality with the restrictive strategy. Furthermore, subgroup analysis showed benefit in various metrics for a restrictive transfusion strategy when adjusting for younger and less-ill patients. This evidence laid the groundwork for our current standard of transfusing to hemoglobin >7g/dL. A restrictive strategy has also been supported by more recent studies. In 2014 the Transfusion Thresholds in Septic Shock (TRISS) study showed no change in 90-day mortality with a restrictive strategy. Additionally, in 2013 the Transfusion Strategy for Acute Upper Gastrointestinal Bleeding study showed reduced 40-day mortality in the restrictive strategy. However, it excluded patients who had massive exsanguination or low rebleeding risk, thus making it difficult to generalize to our patient population. Currently, the Surviving Sepsis Campaign endorses only transfusing RBCs when Hgb <7g/dL unless there are extenuating circumstances such as MI, severe hypoxemia, or active hemorrhage.

References and Further reading:
1. TRISS @ Wiki Journal Club, full text, Georgetown Critical Care Top 40 pages 14-15
2. Transfusion strategy for acute upper gastrointestinal bleeding @ Wiki Journal Club, full text
3. “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016”
4. Wiki Journal Club

Summary by Gordon Pelegrin, MD