The failure of evidence based medicine: A story of chlorthalidone
For those of you who have worked in a pharmacy you might recognize the letters: HCTZ
For those of you who haven’t or do not recognize these letters they represent an abbreviation of the drug hydrochlorothiazide. This is a drug which is lumped into a class called “thiazide” diuretics.
This drug was approved for use in the United States in 1959 and has remained one of the cornerstones of treatment for hypertension. It is combined with over 28 different drugs as well to reduce pill burden.
In fact if you ask most healthcare professionals and students of those programs to identify a diuretic used for hypertension, HCT Z will be the answer. Furthermore, in 2010, HCTZ was the diuretic of choice in >95% of all oral diuretic prescriptions. It must be superior.
Do you recognize these letters: CTD?
Have you heard about a drug called “chlorthalidone?”
This drug was approved for use in the United States in 1960 and has remained one of the forgotten treatments for hypertension. It is combined with only 3 different drugs to reduce pill burden. If you ask most healthcare professionals and students of those programs to identify a thiazide diuretic used for hypertension that is not HCTZ, I am doubtful a response will be easily rendered. Furthermore, in 2010, CTD was the diuretic of choice in only 3% of all oral diuretic prescriptions. It must be inferior.
How does one measure superiority or inferiority? Well I would argue that the drug must show better efficacy and either the same or reduced amount of toxicity. If you are interested in “cost-effectiveness” then you can factor those considerations in as well.
Here are the facts:
Small trials initially (1964) indicated the CTD showed equal efficacy, in lowering blood pressure, to HCTZ at much lower doses.
- CTD more effective?
The Multiple Risk Factor Intervention Trial (MRFIT) started a few years later and participating clinics were given a choice of CTD or HCTZ. Nine chose HCTZ and 6 chose CTD. However, the advisory board recommended after 4 years of study that clinic using HCTZ should switch to CTD because the mortality trend was unfavorable in those clinics using HCTZ and trends were favorable in CTD clinics.
- CTD more effective?
Three additional large trials show positive results for CTD. These included the Systolic Hypertension in Elderly Persons (SHEP) trial (1991), the Verapamil in Hypertension and Atherosclerosis study (1997) and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (2002).
- CTD more effective
In a similar timeframe, in multiple trials, no study documented a benefit for HCTZ.
- HCTZ less effective?
In long-term (>22 years) follow-up of the SHEP trial, CTD is shown to increase longevity by one day for every month that you are on the drug.
- CTD effective
So why is HCTZ preferred over CTD? There is no difference in adverse outcomes other than CTD has a greater ability to lower serum potassium concentrations (a difference of 0.23 mmol/L over 48 months).
CTD has documented efficacy in lowering blood pressure to a greater degree compared to HCTZ. CTD reduces systolic and diastolic blood pressure by 1.7 mmHg and 0.8 mmHg greater than HCTZ. CTD has been documented to reduce morbidity and extend longevity while HCTZ has not.
How did such strong evidence based medicine fail the patients?
The answer (in my opinion)…..awareness of use in a series of studies in the VA coupled with the largest pharmaceutical sales force in the world (Merck). CTD was marketed by a small Swiss company called Geigy. The battle on sales was quickly won by Merck and the use of CTD plummeted despite overwhelming clinical evidence of its superiority.
The time is now for Chlorthalidone and I believe evidence based medicine will win this long war. It is unfortunate that millions of patients over the past 50 years have been denied this intervention. My hope is that the future will change.