Author + information
- Anil K. Pareek, MD,
- Franz H. Messerli, MD∗ ( and )
- Nitin B. Chandurkar, MPharma
- ↵∗Division of Cardiology, Mount Sinai Health Medical Center, Icahn School of Medicine, 1 Gustave L. Levy Place, New York, New York 10029
We thank Dr. Tschanz and colleagues for their interest in our paper (1) and agree that adherence problems in randomized controlled trials often lead to untestable assumptions about treatment groups. The intention-to-treat analysis is more likely to yield a type 2 error (i.e., to find no difference between treatment groups). Hence, it is important to understand the impact of protocol violations on the primary outcome measure. In our study, we had 6 cases of protocol violations, 2 in each treatment arm. Two protocol violation case subjects from the chlorthalidone group completed the study until the baseline visit, whereas the remaining 4 patients from the hydrochlorothiazide and hydrochlorothiazide-CR groups completed the study through week 4. None of the protocol violations, irrespective of the treatment they received, were likely to have had an impact on the primary outcome measure of the study.
To justify our point, we reanalyzed the reported parameters for all randomized patients who had no protocol violation (n = 48) (Table 1). Regarding the concern about fewer patients completing the study, we wish to state that the primary outcome measure of this study was to assess change in mean 24-h ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to week 4 and week 12. Because the maximum fall in blood pressure (BP) occurred within the first 4 weeks of therapy, the 3 treatment arms can also be compared at week 4.
Hence, we also analyzed the data for patients who completed the study until week 4 without any protocol violation (n = 39), assuming the trial was terminated at week 4. Patients treated with chlorthalidone showed a significant reduction in 24-h ambulatory, daytime, and nighttime SBP and DBP at week 4 and week 12. No such significant reduction was observed in patients treated with hydrochlorothiazide, except for a reduction in daytime SBP at week 12. The mean 24-h SBP at week 4 and week 12, mean daytime SBP at week 12, and mean nighttime SBP at week 4 were significantly lower in patients treated with chlorthalidone than in those treated with hydrochlorothiazide. In contrast to hydrochlorothiazide, hydrochlorothiazide-CR showed a significant reduction in 24-h ambulatory BP, daytime BP, and nighttime BP at week 4 and week 12. Thus, it is evident that treatment with chlorthalidone 6.25 mg resulted in a statistically significant reduction in mean 24-h ambulatory BP, daytime BP, and nighttime BP.
We conclude that after analyzing the data in various ways, the principal findings of the study remain unchanged: Chlorthalidone at a very low dose of 6.25 mg is more effective than hydrochlorothiazide 12.5 mg in reducing daytime, nighttime, and 24-h ambulatory BP at week 4 and week 12.
Please note: Dr. Messerli is a consultant for or has consultant/advisory relationships with Daiichi-Sankyo, Pfizer, Takeda, Abbott, AbbVie, Servier, Medtronic, Ipca Laboratories, and Menarini. Dr. Pareek and Mr. Chandurkar are employees of Ipca Laboratories Limited, Mumbai, India.
- American College of Cardiology Foundation