Efficacy and safety of early versus late titration of fixed-dose irbesartan/hydrochlorothiazide: ACTUAL study

Abstract

Hypertension management guidelines recommend titrating antihypertensive drugs stepwise every 4–6 weeks. We compared efficacy and safety of early versus late titration after 10 weeks’ treatment with irbesartan/hydrochlorothiazide. Hypertensive patients uncontrolled on monotherapy were randomized into two groups. In the early titration group (E), patients received irbesartan/hydrochlorothiazide 150/12.5 mg for 2 weeks; uncontrolled patients were up-titrated to 300/25 mg at weeks 2 and 6. In the late titration group (L), patients received 150/12.5 mg for 6 weeks; uncontrolled patients were up-titrated to 300/25 mg at week 6 (W6). The change of mean systolic (SBP) and diastolic blood pressure (DBP) from baseline to week 10 (W10) were studied using a covariance analysis model. The percentage of controlled patients at W10 was compared between groups using Fisher's exact test. Of 833 patients enrolled from 14 countries, the intent-to-treat (ITT) population included 795 (mean age 58 ± 12 years, female 60%, obesity 38%, diabetes 22%). At W6, mean SBP decrease was: E − 28.8 mmHg vs L − 26.3 mmHg (p = 0.02). At W10, there was similar mean SBP decrease: E − 29.5 mmHg vs L − 31.0 mmHg (p = 0.14). The control rate at W10 was 58% (E) and 64% (L), p = 0.06. Serious adverse events were more frequent in E (2.5% vs 0.7%, p = 0.044). Both early and late titration regimens provide similar BP decrease and control rate.

Key Words::

• early titration
• efficacy
• hydrochlorothiazide
• hypertension
• irbesartan
• safety

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Efficacy and safety of early versus late titration of fixed-dose Irbesartan/hydrochlorothiazide: ACTUAL study

Acknowledgements

Bristol-Myers Squibb Company was responsible for the worldwide safety database for irbesartan/HCTZ.

Editorial support for preparing this manuscript was provided by Dr Sujata Shah, Ms Anahita Gouri, and Mr Satyendra Shenoy of sanofi-aventis (India).

The study protocol was prepared by Dr Nathalie Genes, who was employed by sanofi-aventis.

We would like the following investigators, who participated in the ACTUAL Study: Algeria: Nora Henine, Brahim Kichou, Belkacem Benbouabdallah, Mohamed Foughali, Abdelmounène Mekarnia, Zahoua Belkadi, Boudfer and Benkouar; Argentina: Claudio Rodolfo Majul, Hugo Daniel Sanabria, Daniel Leonardo Piskorz, Ricardo Gabriel López Santi, Marcelo Orías, Carlos Alberto Mario Borrego, Olga Beatriz Liliana Paéz, Pablo Alejandro Puleio, Miguel Visser, Cesar Javier Zaidman, Miguel Aron Cartía, Luis Esteban Keller, Carlos Enrique Lamas, María Rosa Siegel, Hugo Gabriel Tonín, Graciela Rosana Reyes, Pablo Gabriel Romia, Julio Oscar Bono, Patricia M. Flammia, Pablo Antonio Novoa, Eduardo Moreyra, Viviana Elizabeth Arias, María Victoria Borrego and Hector Ballestero; Brazil: Décio Mion Jr., Celso Amodeo, Fernando Almeida, Hilton Chaves, José Saraiva, Osvaldo Kohlmann, Paulo Jardim, Wille Oigman, Katia Ortega, Murilo Coelho, Carolina Gonzaga, Márcio Sousa, Maria Valéria Pavan, José Roberto Silva, Maria Helena Vidotti, Frida Plavnik, Marcelo Uehara, Thiago Jardim, Weimar Souza and Mário Fritsch; Colombia: Julio Cesar Duran, Miguel Urina, Alonso Merchan, Carlos Silva, Andres Almanzar, Jose Balaguera and Stase Slotkus; Ecuador: Mayra Sánchez, Carlos Chacón, Alfredo Luna and Luis Falconí; Egypt: Ramez Raouf Guindy, Sameh Mohamed Shaheen, Hossam El-Din Ghanem El-Hossary, Hossam Ibrahim Kandil, Ahmed Shawky El-Serafy, Ahmed Ashraf Eissa, Mohamed Abd El-Lateef Khaleel and Yasser Abd El-Hameed Sharaf; Lebanon: Adel Berbari, Roland Kassab, Georges Ghanem, Chaouki Abdallah, Samer Kabbani, Georges Badawi, Antoine Sarkis and Rabih Azar; Mexico: Miguel Esteban Estrella Garza, Joel Rodríguez Saldaña, Jorge Carrillo Calvillo, Ricardo Alvarado Ruiz, Fernando Antonio Reyes Cisneros, Raúl Gerardo Velasco Sánchez, Edmundo Alfredo Bayram Llamas, René Narvaez David, Eduardo Santiago Uruchurtú Chavarín, Osvaldo Corona, Gregorio Magno Fernández, Hugo López, Marco Antonio Morales de Teresa, José Luis Leiva Pons, Natalia Nikitina, Paulina Sida Pérez, Francisco Javier Robles, Roberto Orozco and Joel Dorantes García; Morocco: Saadia Abir, Said Chraibi, Hafid Akoudad, Laila Azzouzi and Ikram Lahlou; Peru: José Tordoya, Carlos Chavez, Walter Yañez, Mario Carrión, Juan Urquiaga, Victor Herrera, Javier Chumbe and Yudi Roldan; Saudi Arabia: Abdulrahman Ziada, Ibrahim Wasfy, Mohamed Said El Nazer, Yousef Maleeh, Hesham Yehia and Samy Abdel Rahman; Tunisia: Lotfi Slimen, Habib Haouala, Ali Ben Khalfalla, Faouzi Maatouk, Samir Kammoun, Salem Kachboura, Lahidheb Dhaker, Saidi Imen, Othman Salah, Gommidh Mehdi, Samia Chaouachi, Hamrouni Mounir, Leila Abid, Faten Triki and Chine Samira; United Arab Emirates: Al Mahmeed, Binbrek, Agrawal, Sabry, Misra and Munther; and Venezuela: Gloria Vergara, Lempira Guevara, Luis López Gómez, Andrés Carmona, Aaron Cohen, Carlos Mogollón and José Félix Oletta.

Information about previous presentations of the work presented in the article

None.

Sources of support

The ACTUAL study was sponsored by sanofi-aventis.

Conflict of interest statement

Professor Xavier Girerd received honorarium from sanofi-aventis, Daiichi-Sankyo, IPSEN, Novartis Pharma, and Boehringer Ingelheim France during the past 3 years. Dr Joseph Aoun is employed by sanofi-aventis. Dr David Rosenbaum declared no financial disclosure.

Clinical Trials Registry (clinicaltrials.gov) Number

NCT00708344