Table 1.
List of clinical trial comparing the effect of adjuvant anti-coagulant drugs to control (no-treatment or placebo treatment) in terms of cancer progression, metastatic disease, and survival.
| Family of drugs and mechanism of action | Drug tested | Clinical design | Treatment arms | Effect on cancer progression | Effect on survival | Reference | ||
|---|---|---|---|---|---|---|---|---|
| Observation | Outcomes | Observation | Outcomes | |||||
|
Vitamin K antagonists
Inhibition of Vitamin K epoxide reductase, limiting activation of vitamin k-dependent coagulation factors. |
Warfarin | Randomized control clinical trial. n = 431 patients with solid cancers. |
Warfarin (n = 215); no treatment (n = 216). | No difference in disease-free survival and incidence of disease progression, with the exception of small cell lung cancer patients. More metastasis (12 sites) and less metastasis (14 sites) in the warfarin group vs. control group. |
No difference in survival, with the exception of small cell lung cancer patients. | OS = 49.5 weeks (warfarin) vs. 23 weeks (control) | (258) | |
| Warfarin | Prospective randomized trial. n = 294 patients with small cell lung cancer receiving chemotherapy, followed up for 36 months. |
Warfarin (n = 103); no anti-coagulants (n = 86). | Higher rate of disease free survival. | CR = 17% (warfarin) vs. 8% (control) | Prolonged survival. | OS = 9.3 months (warfarin) vs. 7.9 months (control) | (259) | |
| Warfarin | Randomized clinical trial. n = 311 women with metastatic breast cancer receiving chemotherapy. |
Warfarin (n = 152); placebo (n = 159). | No difference in survival. | Survival rate = 57% (warfarin) vs. 63% (placebo) | (260) | |||
| Warfarin | Randomized clinical trial. n = 183 patients with small cells lung cancer receiving chemotherapy, followed up for 69 months. |
Warfarin (n = 91); no anti-coagulants (n = 92). | No difference in disease-free survival rate (CR) and duration (DFS). Non-significant increased rate of distant relapse. |
CR = 74% (warfarin) vs. 83% (control) DFS = 13.7 months (warfarin) vs. 24.0 months (control) Rate of relapse = 33% (warfarin) vs. 19% (control) |
Non-significant increase in survival. | OS = 21.4 months (warfarin) vs. 18.6 months (control) | (261) | |
| Warfarin or acenocoumarol | Observational cohort study. n = 76,008 patients, observed for 8.2 years. |
VKAs (n = 3,231); controls (n = 72,777). | No effect on cancer progression. | RR = 0.85 (95% CI, 0.65–1.12) | Higher mortality. | HR = 1.12 (95% CI, 1.05–1.19) | (262) | |
| Warfarin | Meta-analysis of the Finnish Randomized Study of Screening for Prostate Cancer. n = 6, 537 men with prostate cancer, followed up for 14 years. |
Warfarin (n = 1,210); no anti-coagulants (n = 5,327). | Higher risk of high-grade cancer. Higher risk of metastatic cancer. |
HR = 1.11 (95% CI, 1.04–1.36) HR = 1.48 (95% CI, 1.01–2.17) |
(263) | |||
|
Low molecular weight heparins
Activation of antithrombin III, leading to inhibition of factor Xa and thrombin. |
Dalteparin | Randomized clinical trial. n = 84 patients with small cell lung cancer. |
Dalteparin (n = 42); no anti-coagulants (n = 42). | Increased progression-free survival rate. | 1–2 year PFS rate = 30.4–3.4% (dalteparin) vs. 11.7–0% (control) | Increased survival. Reduced risk of death. |
1–2 year OS rate = 51.3–17.2% (deltaparin) vs. 29.5–0.0% (control) HR = 0.56 (95% CI, 0.3–0.86) |
(264) |
| Dalteparin | Randomized double-blind placebo-controlled trial. n = 385 patients with advanced cancer. |
Dalteparin (n = 190); placebo (n = 184). | Increased survival. | 1–2–3 year OS rate = 46–27–21% (deltaparin) vs. 41–18–12% (control) | (265) | |||
| Nadroparin | Double-blind study. n = 302 patients with advanced solid tumors, followed for up to 1 year. |
Nadroparin (n = 148); placebo (n = 154). | Reduced overall mortality. | HR = 0.75 (95% CI, 0.59–0.96) | (266) | |||
| Nadroparin | Randomized open-label study. n = 503 patients with non-small-cell lung cancer (stage IIIB), hormone-refractory prostate cancer or locally advanced pancreatic cancer. |
Nadroparin (n = 244); no anti-coagulants (n = 259). | No effect on cancer progression. | Time to progression = 5.0 months (nadroparin) vs. 5.8 months (control) | Non-significant prolonged survival. No difference in overall mortality. |
Median survival = 13.1 months (nadroparin) vs. 11.9 months (control) HR = 0.86 (95% CI, 0.67–1.10) |
(267) | |
| Nadroparin |
Post-hoc analyses of randomized double-blind placebo-controlled trial. n = 1,166 ambulatory patients with solid cancer, followed up for 111–113 days. |
Nadroparin (n = 779); placebo (n = 387). | Increased survival in patients with disease control. | 1-year survival rate = 83% (nadroparin) vs. 76% (placebo) | (268) | |||
| Deltaparin | Randomized clinical trial. n = 2,202 patients with lung cancer, followed up for 23.1 months. |
Dalteparin (n = 1,101); no anti-coagulants (n = 1,101). | No difference in the risk of metastasis. No difference in metastasis-free survival. |
HR = 0.99 (95% CI, 0.91–1.08) HR = 1.01 (95% CI, 0.93–1.1) |
(269) | |||
| Tinzaparin | Randomized clinical trial. n = 549 patients with non-small cell lung cancer, followed up for 5.7 years. |
Tinzaparin (n = 269); no anti-coagulants (n = 280). | No difference in overall survival. | HR = 1.24 (0.92–1.68) | (270) | |||
|
NSAIDs
Cyclooxygenase inhibitors. COX-1 inhibition results in an anti-thrombotic effect, COX-2 inhibition results in an anti-inflammatory effect. |
Aspirin | Meta-analysis of case-control studies. n = 141,577 patients with cancer exposed or not to aspirin. |
Reduced risk of cancer with distant metastasis. No difference in risk of regional spread. |
OR = 0.69 (95% CI, 0.57–0.83) OR = 0.98 (95% CI, 0.88–1.09) |
(271) | |||
| Aspirin | Meta-analysis of randomized controlled trials. n = 17,285 patients with or without cancer, treated with aspirin (>75 mg/day) or placebo. | Reduced risk of cancer with distant metastasis, irrespective of initial diagnosis. Reduced risk of metastasis in patients with no metastasis at initial diagnosis. |
HR = 0.74 (95% CI, 0.48–0.84) HR = 0.45 (95% CI, 0.28–0.72) |
Lower rate of death due to cancer. | HR = 0.71 (95% CI, 0.57–0.90) | (22) | ||
| NSAIDs | Meta-analysis of previous clinical studies. n = up to 247,826 patients with cancer exposed or not exposed to NSAIDs. |
Reduced risk of distant metastasis. Slightly reduced risk of lymph node metastasis. |
RR = 0.623 (95% CI, 0.515–0.753) RR = 0.949 (95% CI, 0.914–0.985) |
(272) | ||||
| Celecoxib | Randomized control trial. n = 200 patients with metastatic or advanced gastric cancer. |
Celecoxib (n = 100); no anti-coagulants (n = 100). | Longer progression-free survival of COX-2+ patients. | PFS = 7.5 months (celecoxib) vs. 5 months (control) | Longer overall survival of COX-2+ patients. | OS = 14 months (celecoxib) vs. 10 months (control) | (273) | |
| Mixed anti-coagulants | Anti-coagulant therapy (aspirin, warfarin, clopidogrel, and enoxaparin). | Case-control study. n = 5,955 patients with prostate cancer, followed up for 70 months. |
Anti-coagulants (n = 2,175); no anti-coagulants (n = 3,780). | Lower risk of disease recurrence. Lower risk of bone metastasis. |
7–10 year disease recurrence rate = 24–28% (anti-coagulant) vs. 28–36% (control) 7–10 year bone metastasis rate = 1–3% (anti-coagulant) vs. 3–6% (control) |
Lower risk of prostate cancer specific mortality. Lower risk of prostate specific mortality in the aspirin-user group. |
7–10 year mortality rate = 1–3% (anti-coagulant) vs. 3–8% (control) HR = 0.43 (95% CI, 0.21–0.87) |
(274) |
Patients were treated with concomitant chemotherapy, radiotherapy, and/or surgery as described in the referred papers. Clinical trials with VTE as only endpoint or comparing different anti-coagulants are not listed here. CR, complete response; DFS, disease free survival; HR, hazard ratio; OR, odds ratio; RR, risk ratio; CI, confidence intervals.