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Hydralazine/isosorbide dinitrate

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Hydralazine/isosorbide dinitrate
Combination of
Isosorbide dinitrateVasodilator
HydralazineAntihypertensive
Clinical data
Trade namesBidil
License data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
ChemSpider
KEGG
CompTox Dashboard (EPA)
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Hydralazine/isosorbide dinitrate, sold under the brand name Bidil, is a fixed-dose combination medication used to treat self-identified Black people with congestive heart failure.[1] It is a combination of hydralazine hydrochloride (an arteriolar vasodilator) and isosorbide dinitrate (a nitrate vasodilator).[1][2]

The US Food and Drug Administration (FDA) approved medication to treat congestive heart failure in specifically self-identified Black patients. It provoked controversy as the first drug approved by the FDA marketed for a single racial-ethnic group.[3]

History

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From 1980 to 1985, Dr. Jay Cohn of the University of Minnesota led a clinical trial in collaboration with the US Veterans Administration called the Vasodilator-Heart Failure Trial (V-HeFT I) that tested whether the combination of isosorbide dinitrate and hydralazine increased survival in patients with heart failure. The results were promising and a follow-up study, V-HeFT II, tested the novel combination against enalapril.[4] Cohn applied for a patent on the combination treatment, which was issued in 1989 as US Patent 4868179.[5] Cohn then licensed the patent to Medco Pharmaceuticals who went on to prepare a New Drug Application (NDA) to approve BiDil on the basis of the V-HeFT trials.[4]

The V-HeFT data was re-analyzed and found that the drug combination appeared to be more effective in treating self-identified African-Americans. This was a significant finding due to prior studies which showed that African-Americans with congestive heart failure (CHF) appeared to respond less effectively to conventional CHF treatments (particularly ACE inhibitors) than White Americans.[6] A new paper was published on these findings and MedCo filed for a new patent for the drug as a treatment for heart failure specifically in black patients.[4][7][8]

The new patent and the old patent were then licensed to a company called NitroMed, which ran a clinical called the African-American Heart Failure Trial (A-HeFT), the results of which were published in 2004 in the New England Journal of Medicine.[9] The clinical trial was stopped early because the drug showed significant benefit; it reduced mortality by 43%, reduced hospitalizations by 39%, and improved quality of life markers in African-American patients with CHF.[9]

On the basis of A-HeFT, the FDA approved BiDil in June 2005.[4][10][11] In 2006, the Heart Failure Society of America included the use of the fixed dose combination of isosorbide dinitrate/hydralazine as the standard of care in the treatment of heart failure in Black patients.[12]: e44 

Society and culture

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Controversy

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The new drug application claiming treatment of a single, self-identified racial group raised a storm of controversy. Some hailed the development of BiDil as a breakthrough for Black Americans (such groups included the congressional Black Caucus, the Association of Black Cardiologists, the National Medical Association, and the National Association for the Advancement of Colored People) and a step to addressing the unique health care needs and health disparities of the African American community.[13]

Others who criticized the preliminary studies argued that the original study did not have a significant number of African-American subjects to make the BiDil's race specific claims,[13]: 171  and that the results of only one clinical trial where African-Americans were tested does not provide a full and comprehensive study.[13]: 174  Furthermore, critics argued that self-identified racial identifications from patients as an indicator for race during the trials were not a sufficient categorization method because these self-identifications were socially constructed and have no biological connection to genomic data.[13]: 175  They argued that the trials represented a new form of scientific racism where race, a socially constructed category, would continue to be present in research as a placeholder for genomic identification.[4][14][15][16][17][18]

The A-HeFT trial has been the subject of further criticism due to its study design that failed to include a non-African American test group to control for racial factors.[19] According to Jay Cohn, the pill's developer, the reason for including only African American test subjects was the lack of funding for doing a trial in the full population.[20]

References

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  1. ^ a b c "Bidil- hydralazine hydrochloride and isosorbide dinitrate tablet, film coated". DailyMed. U.S. National Library of Medicine. 26 January 2021. Retrieved 11 April 2022.
  2. ^ Ferdinand KC, Elkayam U, Mancini D, Ofili E, Piña I, Anand I, et al. (July 2014). "Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the African-American Heart Failure Trial". The American Journal of Cardiology. 114 (1): 151–159. doi:10.1016/j.amjcard.2014.04.018. PMID 24846808.
  3. ^ Whitmarsh I, Jones DS, eds. (2010). "Governance and the Uses of Race" (PDF). What's the Use of Race?: Modern Governance and the Biology of Difference. Cambridge, MA: MIT Press. ISBN 978-0-262-51424-8. Archived from the original (PDF) on 5 March 2016. Retrieved 8 December 2013.* Panizzo R (21 November 2011). "Book Review: What's the Use of Race? Modern Governance and the Biology of Difference". BioNews. No. 634.
  4. ^ a b c d e Kahn J. "Chapter 7: BiDil and Racialized Medicine". In Krimsky S, Sloan K (eds.). Race and the Genetic Revolution: Science, Myth, and Culture. Columbia University Press. doi:10.7312/krim15696-008. ISBN 978-0-231-52769-9.
  5. ^ US 4868179, Cohn JN, "Method of reducing mortality associated with congestive heart failure using hydralazine and isosorbide dinitrate", issued 19 September 1989, assigned to Department of Veterans Affairs 
  6. ^ Exner DV, Dries DL, Domanski MJ, Cohn JN (May 2001). "Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction". The New England Journal of Medicine. 344 (18): 1351–1357. doi:10.1056/NEJM200105033441802. PMID 11333991.
  7. ^ Carson P, et al. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group J Card Fail. 1999 Sep;5(3):178-87.
  8. ^ US 6465463, Cohn JN, Carson P, "Methods of treating and preventing congestive heart failure with hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate", issued 15 October 2002, assigned to Nitromed Inc. and Arbor Pharmaceuticals LLC 
  9. ^ a b Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, et al. (November 2004). "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". The New England Journal of Medicine. 351 (20): 2049–2057. doi:10.1056/NEJMoa042934. PMID 15533851. S2CID 12012042.
  10. ^ "Bidil (Isosorbide Dinitrate and Hydralazine Hydrochloride) Tablets". Drug Approval Package. U.S. Food and Drug Administration.
  11. ^ "FDA Approves BiDil Heart Failure Drug for Black Patients". U.S. Food and Drug Administration. 23 June 2005. Archived from the original on 8 July 2005.
  12. ^ Adams KF, Lindenfeld JA, Arnold JM, Baker DW, Barnard DH, Baughman KL, et al. (February 2006). "HFSA 2006 comprehensive heart failure practice guideline" (PDF). Journal of Cardiac Failure. 12 (1): e1-22. doi:10.1016/j.cardfail.2005.11.005. PMID 16500560. Archived from the original (PDF) on 28 July 2011.
  13. ^ a b c d Roberts D (2011). "Chapter 8: The Color Coded Pill". Fatal Invention: How Science, Politics, and Big Business Re-create Race in the Twenty-first Century. New York: The New Press. ISBN 978-1-595-58834-0.
  14. ^ "Race and Medicine". Radiolab. WNYC. 28 November 2008. Archived from the original on 31 January 2009. Audio story about racial issues surrounding Bidil.
  15. ^ "Race-Based Medicine: A Recipe for Controversy". Scientific American. 31 July 2007.
  16. ^ Kahn J (1 August 2007). "Race in a Bottle". Scientific American. 297 (2): 40–45. Bibcode:2007SciAm.297b..40K. doi:10.1038/scientificamerican0807-40. S2CID 119514435. Article criticizing approval of Bidil.
  17. ^ "BiDil Maker NitroMed Responds to "Race In A Bottle" The Science Behind BiDil". Scientific American. 30 July 2007.
  18. ^ "Response for FDA's Robert Temple to Scientific American article". FDA Web Review.
  19. ^ Puckrein G (2006). "BiDil: From Another Vantage Point". Health Affairs. Archived from the original on 22 March 2015. Retrieved 1 October 2013.
  20. ^ Saini A (2019). Superior: The Return of Race Science. Beacon Press. p. 246. ISBN 978-0807076910.
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