- Email: [email protected]
Survival After Solid Cancers in Antithrombotic Trials
Survival After Solid Cancers in Antithrombotic Trials Victor L. Serebruany, MD, PhDa,*, Ales Tomek, MDb, and Moo Hyun Kim, MD, PhDc The impact of antithrombotics on cancer is currently under intense investigation because of the excess of solid cancers in trials after thienopyridines such as TRITON (prasugrel), DAPT (prasugrel and clopidogrel), PAR-1 thrombin antagonist in TRACER (vorapaxar), pyrimidines in PEGASUS (ticagrelor), and in APPRAISE-2 after apixaban. However, whether patient survival after solid cancer (SASC) in antithrombotic trials may be affected is unknown. We matched the 1-year SASC rate in antithrombotic trials reported by Food and Drug Administration with the census averages in Surveillance, Epidemiology, and End Results (SEER) Program by the US National Cancer Institute and World Health Organization (WHO) surveys. The Food and Drug Administration provided the SASC data for 3 trials with similar cancer survival of about 70% for the first year of follow-up in TRITON, APPRAISE-2, and ARISTOTEL. Adjusted cancers in TRITON with SEER (odds ratio 0.92; 95% confidence interval 0.53 to 1.59, p [ 0.4351) and WHO (odds ratio 0.99; 95% confidence interval 0.57 to 1.7, p [ 1.00) revealed very close if not identical SASC rates in antithrombotic trials compared to epidemiologic census estimates. In conclusion, SASC rates in patients enrolled in antithrombotic trials do not differ from SEER or World Health Organization averages. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;116:969e972) The link between malignancy and hemostasis is not new.1,2 The first alarming signal that antiplatelet therapy may cause excess of solid cancers was observed in the prasugrel arm of TRITON-TIMI 38 trial3 and confirmed by the Food and Drug Administration (FDA).4 Later, until TRACER FDA review,5 the data remain inconclusive, probably because of the awareness of drug manufacturers of such catastrophic association resulted in missing delayed outcomes, discontinuations, or/and incomplete follow-up, suggesting bias. Recently, however, 4 important pieces of the puzzle emerge, namely vorapaxar, apixaban FDA reviews,5,6 DAPT7 for clopidogrel and prasugrel, and PEGASUS8 for ticagrelor confirming that cancer signal after antithrombotics is not an artifact, or play of chance, but rather a scaring reality. Independently, a Danish registry for almost 126,000 myocardial infarction (MI) survivors without a history of cancer were matched with more than 3 million subjects with no history of either MI or cancer. Results suggested that cancer rate was more than doubled (173.5 per 10,000 person-years) in the MI survivors versus 85.2 per 10,000 person-years for their peers without MI over 17-year follow-up.9 Despite the existing cancer signal, survival of such patients may be worsened because chronic antithrombotic regimens may cause not only more cancer dissemination but promotion of more aggressive unclassified malignancies10 associated with potentially shorter survival. We, therefore, matched the survival after solid cancers in TRITON prasugrel arm with the publically available
a
HeartDrug Research Laboratories, Johns Hopkins University, Baltimore, MD; bUniversity of Prague, Prague, Czech Republic; and cDong-A University, Busan, Korea. Manuscript received March 30, 2015; revised manuscript received and accepted June 14, 2015. See page 972 for disclosure information. *Corresponding author: Tel: (410) 274-2405; fax: (443) 583-0205. E-mail address: [email protected] (V.L. Serebruany). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.06.026
evidence from 2 reputable independent international census datasets. Methods The cancer data for TRITON are readily available for prasugrel New Drug Application review and updated in several later public FDA documents. Two data sets were used as the references. We matched the TRITON evidence with the Surveillance, Epidemiology, and End Results (SEER) Program, issued by the US National Cancer Institute11 and corresponding World Health Organization (WHO) data gathering survival data from 14 regions worldwide.12 For survival comparisons, SEER Survival Database (SEER 13) from 1988 until 2010 has been used adjusting age (>50 years), race (white and Hispanic), gender (both), and corresponding site of cancer location. For incidence data, Age-Adjusted SEER Incidence Rates (SEER 9) with selected year 2009, and similar age, race, gender, and cancer location adjustments were used. Analyses were done with STATA 13 software (StataCorp, College Station, Texas) using unstratified cumulative incidence data function with Fisher’s exact test with computation of 95% confidence interval (CI) and odds ratios (ORs). Results The distribution of 132 solid cancers in prasugrel arm of TRITON trial is presented in Figure 1. The sites for solid cancers in TRITON were broad, and the most prevalent locations were colorectal, lung, prostate, urinary bladder, and stomach. The solid cancer survival curves from the TRITON FDA review are presented in Figure 2. In fact, cancer survival in TRITON did not differ much dependent on treatment assignment and was overall about 70% for 1 year in both clopidogrel and prasugrel arms. Importantly, most registries and large data sets report cancer survival in 5-year increments, representing some difficulties in adjusting the trial data, in www.ajconline.org
970
The American Journal of Cardiology (www.ajconline.org)
Figure 1. Distribution of new cancer locations in TRITON.
routine cardiac catheterization, and, therefore, enrolled in established top medical centers, TRITON cancer survival should be matched much more reasonably with the USgenerated data sets. The differences between actual solid cancers in TRITON after prasugrel and SEER’s modeled data for cancer sites are presented in Table 2. The incidence of new solid cancers in TRITON overall was similar to those in SEER; however, in TRITON, there were significantly more colorectal and stomach and less prostate cancers. Importantly, SEER statistics compare the survival of patients diagnosed with cancer with the survival of people in the general population who are the same age, race, and gender and who have not been diagnosed with cancer. As a limitation, survival statistics are based on large groups of people, they cannot be used to predict exactly what will happen to an individual patient because no 2 patients are entirely alike, and treatment and responses to treatment can vary greatly. Adjusted cancer
Figure 2. Survival after first solid cancer events in TRITON (A), ARISTOTELE (B), and APPRAISE-2 (C).
Table 1 National cancer institute 5-year survival rates for new solid cancers Cancer Location Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarian Stomach Lung Esophagus Oral/pharynx
5-Years Survival US
5-Years Survival Worldwide (range)
98.9% 64.7% 89.2% 77.4%
48-99% 39-65% 73-89% 39-78%
72.4% 6.7% 44.6% 28.3% 16.8% 17.5% 62.7%
45-72% 3-10% 30-45% 15-30% 8-17% 5-19% 48-69%
which the follow-up is usually much shorter and sometimes is even less than 1 year. The 5-year survival rates for new solid cancers based on the SEERSTAT US National Cancer Institute data are presented in Table 1. Not surprisingly, the US survival rates were better than worldwide estimates because the latest include the patients from underdeveloped countries. Because most of the patients in antithrombotic trials require
survival rates observed in TRITON- and SEER-modeled data for cancer locations are presented in Table 3. On the basis of the data in Table 3, considering cancer distribution in TRITON, we can expect 42 fatalities of 132 new cases, leaving 90 patients (68.2%) surviving for the first year after new cancer diagnosis. Applying these data to the KaplaneMeier curves outlined in the FDA report (Figure 1) clearly indicate that of 100% survival at the start of TRITON enrollment or corresponding 76-mm height on the graph, prasugrel curve declines to 53 mm at 12 months, making yearly survival of such patients at 69.7%. Considering the numbers from the same curve at 110 at risk, then 69.7% is 77 of 110 survived for 1 year, making the OR for TRITON patients compared to the SEER model cohort very close and not significantly different (OR 0.9183673; 95% CI 0.53 to 1.59, p ¼ 0.4351). In addition to SEER, we matched the TRITON data with the World Health Organization (WHO) cancer statistics as outlined in Table 4. The data in Table 4 indicate that cancer survival in TRITON adjusted through the WHO model cohort is 92 (69.7%) of 132 prasugrel patients diagnosed with new solid cancers in TRITON. The comparison for TRITON versus WHO cancer survival data exhibited identical rates (OR 0.9857143; 95% CI 0.57 to 1.7, p ¼ 1.00).
Miscellaneous/Cancer Survival During Antithrombotic Therapy
971
Table 2 SEER’s adjusted incidence of cancer locations in TRITON Cancer Site Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarian Stomach Lung Esophagus Oral/pharynx
Solid Cancers*
Incidence (SEER)†
Incidence (TRITON)z
Odds ratio with 95% CI; and p-value
17 29 4 13
524.43 134.93 364.93 78.19
32.38 11.11 7.51 6.44
0.530 2.643 0.499 2.169
9 5 3 14 28 7 3
45.85 43.46 38.17 20.18 208.72 16.72 33.87
3.77 3.58 0.79 1.66 17.18 1.38 2.79
2.252 (0.735 to 6.893, p ¼ 0.267) 1.250 (0.364 to 4.301, p ¼ 1.000) 3.001 (0.348 to 25.855, p ¼ 0.625) 7.012 (1.966 to 25.014, p ¼ 0.004) 1.650 (0.910 to 2.990, p ¼ 0.135) 7.005 (1.160 to 42.306, p ¼ 0.07) Identical, not significant
(0.296 (1.337 (0.160 (0.853
to to to to
0.947, 5.226, 1.560, 5.518,
p p p p
¼ ¼ ¼ ¼
0.044) 0.006) 0.387) 0.167)
* Solid cancers in prasugrel arm of TRITON trial, with the median follow-up of 14.5 months. † Per 100,000 persons per 1 year, year 2009 ages 50þ, whites or Hispanics, both sexes or as appropriate females (breast, ovarian) or males (prostate) via (SEER 9). z TRITON rate modeled by SEER database.
Table 3 Adjusted cancer survival in TRITON and SEER-modeled data
Table 4 Adjusted cancer survival in TRITON and WHO- modeled data
Cancer Site
Cancer Location
Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarian Stomach Lung Esophagus Oral/pharynx Sum
Solid Cancers Relative TRITON Mortality at 1 Year in TRITON Survival at Approximated from SEER (n, %) 1 Year SEER* 17 29 4 13
(12.9%) (22.0%) (3.0%) (9.8%)
99.7% 81.6% 97.5% 90.1%
0 5 0 1
9 5 3 14 28 7 3
(6.8%) (3.8%) (2.2%) (9.0%) (21.3%) (5.2%) (2.2%) 132
79.0% 22.4% 70.8% 46.7% 40.7% 44.8% 82.0%
2 4 1 7 17 4 1 42
* Age 50þ (Surveillance, Epidemiology, and End Results) (SEER) Program (www.seer.cancer.gov) SEER *Stat Database: SEER Survival (1988-2010).
Discussion The main finding of the index study is establishing that despite increase of new solid cancers, and cancer-related deaths in antithrombotic trials, the survival rate of patients with cancer does not differ much, if not appear identical with the US National Cancer Institute or WHO census averages. This finding has been somewhat surprising because more aggressive and deadly cancers concomitant to long-term antithrombotic therapy have been suspected. The available body of evidence indicates that average yearly cancer survival in antithrombotic trials is about 70% matching very closely with national and international epidemiologic data. The most reasonable and likely clinical scenario linking antithrombotic therapy and solid cancer is
Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarial Stomach Lung Esophagus Oral/pharynx Sum
Solid Cancers (n ¼ 132)
Relative survival at 1 year WHO
Mortality at 1 year WHO data
17 29 4 13
97% 86% 96% 95%
0 4 0 1
9 5 3 14 28 7 3 132
N/A; 79% by SEER data 16% 73% 51% 44% 39% 78%
2 4 1 7 16 4 1 40
due to persistent platelet inhibition and/or long-term excessive anticoagulation promoting easier and earlier dissemination of younger unclassified cancer cells enhancing metastatic risks. In lay terms, cancer follows bleeding. As initially observed with prasugrel, the longer we use such therapy, and more aggressive strategy we choose, the more solid cancers will occur. The good news is that antithrombotics as chemical entities can now be exonerated from being unique cancer promoters because cancer signals are now reported for numerous drugs and drug classes. The bad news is that any aggressive regimen impacting hemostasis for a long term holds extra solid cancer risks. Even worse is that solid cancer risks are not exclusively attributed to antiplatelet agents but anticoagulants as well. In fact, solid cancer rates after apixaban did not differ in successful ARISTOTEL but were more than doubled in the halted APPRAISE-2 trial, again suggesting that cancer follows bleeding. The survival rates for both trials with apixaban are
972
The American Journal of Cardiology (www.ajconline.org)
presented in Figure 2. Importantly, cancer survival in apixaban trials was similar to those in antiplatelet study and averages about 70% at 1-year follow-up reassuring that particular TRITON survival rates can be extrapolated to antithrombotics general. Future research should focus on early cancer diagnostics and public awareness. In conclusion, SASC rates in patients enrolled in antithrombotic trials do not differ from SEER or WHO averages. Disclosures Dr. Serebruany is listed as an inventor for the issued US patent “Treating vascular events with statins by inhibiting PAR-1 and PAR-4” (7,842,716) assigned to HeartDrug Research and two pending applications “Treating cardiac arrhythmias, heart failure, peripheral vascular disease, and stroke with cyclopentyl-triazolo-pyrimidine or derivative thereof” (USN 61/253,829), assigned to HeartDrug, and “Method for treatment of platelet activity with E5555” (USN 61/080,791), assigned to Eisai and HeartDrug. Dr. Serebruany received compensation for the issued US. Patent 11/996,380 “Use of PAR-1/PAR-4 inhibitors for treating and preventing vascular diseases” on prasugrel assigned to Lilly. Dr. Serebruany received funding for research studies with clopidogrel and prasugrel and consultant fees from clopidogrel and ticagrelor manufacturers. Other authors have no conflicts of interest to report.
4.
5. 6. 7.
8. 9.
10. 11.
1. Coupland LA, Parish CR. Platelets, selectins, and the control of tumor metastasis. Semin Oncol 2014;41:422e434. 2. Falanga A, Russo L, Milesi V. The coagulopathy of cancer. Curr Opin Hematol 2014;21:423e439. 3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in
12.
patients with acute coronary syndromes. N Engl J Med 2007;357: 2001e2015. Food and Drug Administration. Briefing document, February 3, 2009 Meeting of FDA Cardiovascular and Renal Drugs Advisory Committee on Prasugrel. Available at: http://www.fda.gov/downloads/ advisorycommittees/committeesmeetingmaterials/drugs/cardiovascular andrenaldrugsadvisorycommittee/ucm181185.pdf Accessed on January 16, 2015. NDA 294-886. Cross-discipline Team Leader Review on Vorapaxar 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/ nda/2014/204886Orig1s000SumR.pdf. Accessed on January 17, 2015. Apixaban clinical review. The Food and Drug Administration. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/ 202155Orig1s000MedR.pdf Accessed on January 17, 2015. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155e2166. Malmborg MW, Christiansen C, Gislason G, Schou M. High risk of cancer among survivors of myocardial infarction: A Nationwide Study. Poster 1104/053; ACC 015, San Diego, CA, USA. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Ophuis TO, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791e1800. Serebruany VL, Dinicolantonio JJ, Can MM, Goto S. Unclassified pleomorphic and spindle cell pulmonary neoplasm with brain metastases after prasugrel. Cardiology 2013;124:85e90. Surveillance, Epidemiology, and End Results (SEER) Program Populations (1969-2012) (Available at: www.seer.cancer.gov/popdata), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, accessed on February 27, 2015. Mathers CD, Boschi-Pinto C, Lopez AD, Murray CJL. Cancer incidence, mortality and survival by site for 14 regions of the world. In: Global Programme on Evidence for Health Policy Discussion Paper No. 13. Geneva, Switzerland: World Health Organization; 2001, http:// www.who.int/healthinfo/paper13.pdf. Accessed on March 26, 2015.
a
HeartDrug Research Laboratories, Johns Hopkins University, Baltimore, MD; bUniversity of Prague, Prague, Czech Republic; and cDong-A University, Busan, Korea. Manuscript received March 30, 2015; revised manuscript received and accepted June 14, 2015. See page 972 for disclosure information. *Corresponding author: Tel: (410) 274-2405; fax: (443) 583-0205. E-mail address: [email protected] (V.L. Serebruany). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.06.026
evidence from 2 reputable independent international census datasets. Methods The cancer data for TRITON are readily available for prasugrel New Drug Application review and updated in several later public FDA documents. Two data sets were used as the references. We matched the TRITON evidence with the Surveillance, Epidemiology, and End Results (SEER) Program, issued by the US National Cancer Institute11 and corresponding World Health Organization (WHO) data gathering survival data from 14 regions worldwide.12 For survival comparisons, SEER Survival Database (SEER 13) from 1988 until 2010 has been used adjusting age (>50 years), race (white and Hispanic), gender (both), and corresponding site of cancer location. For incidence data, Age-Adjusted SEER Incidence Rates (SEER 9) with selected year 2009, and similar age, race, gender, and cancer location adjustments were used. Analyses were done with STATA 13 software (StataCorp, College Station, Texas) using unstratified cumulative incidence data function with Fisher’s exact test with computation of 95% confidence interval (CI) and odds ratios (ORs). Results The distribution of 132 solid cancers in prasugrel arm of TRITON trial is presented in Figure 1. The sites for solid cancers in TRITON were broad, and the most prevalent locations were colorectal, lung, prostate, urinary bladder, and stomach. The solid cancer survival curves from the TRITON FDA review are presented in Figure 2. In fact, cancer survival in TRITON did not differ much dependent on treatment assignment and was overall about 70% for 1 year in both clopidogrel and prasugrel arms. Importantly, most registries and large data sets report cancer survival in 5-year increments, representing some difficulties in adjusting the trial data, in www.ajconline.org
970
The American Journal of Cardiology (www.ajconline.org)
Figure 1. Distribution of new cancer locations in TRITON.
routine cardiac catheterization, and, therefore, enrolled in established top medical centers, TRITON cancer survival should be matched much more reasonably with the USgenerated data sets. The differences between actual solid cancers in TRITON after prasugrel and SEER’s modeled data for cancer sites are presented in Table 2. The incidence of new solid cancers in TRITON overall was similar to those in SEER; however, in TRITON, there were significantly more colorectal and stomach and less prostate cancers. Importantly, SEER statistics compare the survival of patients diagnosed with cancer with the survival of people in the general population who are the same age, race, and gender and who have not been diagnosed with cancer. As a limitation, survival statistics are based on large groups of people, they cannot be used to predict exactly what will happen to an individual patient because no 2 patients are entirely alike, and treatment and responses to treatment can vary greatly. Adjusted cancer
Figure 2. Survival after first solid cancer events in TRITON (A), ARISTOTELE (B), and APPRAISE-2 (C).
Table 1 National cancer institute 5-year survival rates for new solid cancers Cancer Location Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarian Stomach Lung Esophagus Oral/pharynx
5-Years Survival US
5-Years Survival Worldwide (range)
98.9% 64.7% 89.2% 77.4%
48-99% 39-65% 73-89% 39-78%
72.4% 6.7% 44.6% 28.3% 16.8% 17.5% 62.7%
45-72% 3-10% 30-45% 15-30% 8-17% 5-19% 48-69%
which the follow-up is usually much shorter and sometimes is even less than 1 year. The 5-year survival rates for new solid cancers based on the SEERSTAT US National Cancer Institute data are presented in Table 1. Not surprisingly, the US survival rates were better than worldwide estimates because the latest include the patients from underdeveloped countries. Because most of the patients in antithrombotic trials require
survival rates observed in TRITON- and SEER-modeled data for cancer locations are presented in Table 3. On the basis of the data in Table 3, considering cancer distribution in TRITON, we can expect 42 fatalities of 132 new cases, leaving 90 patients (68.2%) surviving for the first year after new cancer diagnosis. Applying these data to the KaplaneMeier curves outlined in the FDA report (Figure 1) clearly indicate that of 100% survival at the start of TRITON enrollment or corresponding 76-mm height on the graph, prasugrel curve declines to 53 mm at 12 months, making yearly survival of such patients at 69.7%. Considering the numbers from the same curve at 110 at risk, then 69.7% is 77 of 110 survived for 1 year, making the OR for TRITON patients compared to the SEER model cohort very close and not significantly different (OR 0.9183673; 95% CI 0.53 to 1.59, p ¼ 0.4351). In addition to SEER, we matched the TRITON data with the World Health Organization (WHO) cancer statistics as outlined in Table 4. The data in Table 4 indicate that cancer survival in TRITON adjusted through the WHO model cohort is 92 (69.7%) of 132 prasugrel patients diagnosed with new solid cancers in TRITON. The comparison for TRITON versus WHO cancer survival data exhibited identical rates (OR 0.9857143; 95% CI 0.57 to 1.7, p ¼ 1.00).
Miscellaneous/Cancer Survival During Antithrombotic Therapy
971
Table 2 SEER’s adjusted incidence of cancer locations in TRITON Cancer Site Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarian Stomach Lung Esophagus Oral/pharynx
Solid Cancers*
Incidence (SEER)†
Incidence (TRITON)z
Odds ratio with 95% CI; and p-value
17 29 4 13
524.43 134.93 364.93 78.19
32.38 11.11 7.51 6.44
0.530 2.643 0.499 2.169
9 5 3 14 28 7 3
45.85 43.46 38.17 20.18 208.72 16.72 33.87
3.77 3.58 0.79 1.66 17.18 1.38 2.79
2.252 (0.735 to 6.893, p ¼ 0.267) 1.250 (0.364 to 4.301, p ¼ 1.000) 3.001 (0.348 to 25.855, p ¼ 0.625) 7.012 (1.966 to 25.014, p ¼ 0.004) 1.650 (0.910 to 2.990, p ¼ 0.135) 7.005 (1.160 to 42.306, p ¼ 0.07) Identical, not significant
(0.296 (1.337 (0.160 (0.853
to to to to
0.947, 5.226, 1.560, 5.518,
p p p p
¼ ¼ ¼ ¼
0.044) 0.006) 0.387) 0.167)
* Solid cancers in prasugrel arm of TRITON trial, with the median follow-up of 14.5 months. † Per 100,000 persons per 1 year, year 2009 ages 50þ, whites or Hispanics, both sexes or as appropriate females (breast, ovarian) or males (prostate) via (SEER 9). z TRITON rate modeled by SEER database.
Table 3 Adjusted cancer survival in TRITON and SEER-modeled data
Table 4 Adjusted cancer survival in TRITON and WHO- modeled data
Cancer Site
Cancer Location
Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarian Stomach Lung Esophagus Oral/pharynx Sum
Solid Cancers Relative TRITON Mortality at 1 Year in TRITON Survival at Approximated from SEER (n, %) 1 Year SEER* 17 29 4 13
(12.9%) (22.0%) (3.0%) (9.8%)
99.7% 81.6% 97.5% 90.1%
0 5 0 1
9 5 3 14 28 7 3
(6.8%) (3.8%) (2.2%) (9.0%) (21.3%) (5.2%) (2.2%) 132
79.0% 22.4% 70.8% 46.7% 40.7% 44.8% 82.0%
2 4 1 7 17 4 1 42
* Age 50þ (Surveillance, Epidemiology, and End Results) (SEER) Program (www.seer.cancer.gov) SEER *Stat Database: SEER Survival (1988-2010).
Discussion The main finding of the index study is establishing that despite increase of new solid cancers, and cancer-related deaths in antithrombotic trials, the survival rate of patients with cancer does not differ much, if not appear identical with the US National Cancer Institute or WHO census averages. This finding has been somewhat surprising because more aggressive and deadly cancers concomitant to long-term antithrombotic therapy have been suspected. The available body of evidence indicates that average yearly cancer survival in antithrombotic trials is about 70% matching very closely with national and international epidemiologic data. The most reasonable and likely clinical scenario linking antithrombotic therapy and solid cancer is
Prostate Colorectal Breast Urinary Bladder Kidney Pancreas Ovarial Stomach Lung Esophagus Oral/pharynx Sum
Solid Cancers (n ¼ 132)
Relative survival at 1 year WHO
Mortality at 1 year WHO data
17 29 4 13
97% 86% 96% 95%
0 4 0 1
9 5 3 14 28 7 3 132
N/A; 79% by SEER data 16% 73% 51% 44% 39% 78%
2 4 1 7 16 4 1 40
due to persistent platelet inhibition and/or long-term excessive anticoagulation promoting easier and earlier dissemination of younger unclassified cancer cells enhancing metastatic risks. In lay terms, cancer follows bleeding. As initially observed with prasugrel, the longer we use such therapy, and more aggressive strategy we choose, the more solid cancers will occur. The good news is that antithrombotics as chemical entities can now be exonerated from being unique cancer promoters because cancer signals are now reported for numerous drugs and drug classes. The bad news is that any aggressive regimen impacting hemostasis for a long term holds extra solid cancer risks. Even worse is that solid cancer risks are not exclusively attributed to antiplatelet agents but anticoagulants as well. In fact, solid cancer rates after apixaban did not differ in successful ARISTOTEL but were more than doubled in the halted APPRAISE-2 trial, again suggesting that cancer follows bleeding. The survival rates for both trials with apixaban are
972
The American Journal of Cardiology (www.ajconline.org)
presented in Figure 2. Importantly, cancer survival in apixaban trials was similar to those in antiplatelet study and averages about 70% at 1-year follow-up reassuring that particular TRITON survival rates can be extrapolated to antithrombotics general. Future research should focus on early cancer diagnostics and public awareness. In conclusion, SASC rates in patients enrolled in antithrombotic trials do not differ from SEER or WHO averages. Disclosures Dr. Serebruany is listed as an inventor for the issued US patent “Treating vascular events with statins by inhibiting PAR-1 and PAR-4” (7,842,716) assigned to HeartDrug Research and two pending applications “Treating cardiac arrhythmias, heart failure, peripheral vascular disease, and stroke with cyclopentyl-triazolo-pyrimidine or derivative thereof” (USN 61/253,829), assigned to HeartDrug, and “Method for treatment of platelet activity with E5555” (USN 61/080,791), assigned to Eisai and HeartDrug. Dr. Serebruany received compensation for the issued US. Patent 11/996,380 “Use of PAR-1/PAR-4 inhibitors for treating and preventing vascular diseases” on prasugrel assigned to Lilly. Dr. Serebruany received funding for research studies with clopidogrel and prasugrel and consultant fees from clopidogrel and ticagrelor manufacturers. Other authors have no conflicts of interest to report.
4.
5. 6. 7.
8. 9.
10. 11.
1. Coupland LA, Parish CR. Platelets, selectins, and the control of tumor metastasis. Semin Oncol 2014;41:422e434. 2. Falanga A, Russo L, Milesi V. The coagulopathy of cancer. Curr Opin Hematol 2014;21:423e439. 3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in
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