Proactive multiple cardiovascular risk factor management compared with usual care in patients with hypertension and additional risk factors: the CRUCIAL trial

Abstract

Objective:

To investigate whether a proactive multifactorial risk factor intervention strategy using single-pill amlodipine/atorvastatin (5/10, 10/10 mg) in addition to other antihypertensive and lipid-lowering therapy, as required, resulted in greater reduction in calculated Framingham 10-year coronary heart disease (CHD) risk compared with usual care (UC) after 52-weeks treatment.

Research design and methods:

Prospective, multinational, open-label, cluster randomized trial, with the investigator as the unit of randomization. Eligible hypertensive patients were 35–79 years of age, with ≥3 additional cardiovascular risk factors, but no history of CHD and baseline total cholesterol (TC) ≤6.5 mmol/l.

Clinical trial registration:

Trial registration: ClinicalTrials.gov identifier: NCT00407537.

Main outcome measure:

The primary endpoint was calculated Framingham 10-year CHD risk at 52 weeks.

Results:

Of the 140 randomized sites, 136 sites contributed 1461 patients. Mean baseline age and low-density lipoprotein cholesterol (LDL-C) were comparable between treatment arms. Mean baseline BP (150.3/89.7 vs. 144.3/86.5 mmHg) and Framingham CHD risk (20.0 vs. 18.1%) were higher in the proactive intervention versus the UC arm (p < 0.002 for both). At week 52, mean CHD risk was 12.5% in the proactive intervention arm and 16.3% in the UC arm (p < 0.001). The difference, observed at weeks 16 and 52, was primarily driven by significant differences in systolic BP and in TC between the two arms. Overall, adverse events (AEs) were reported in 48.8% and 44.0% of patients in the proactive intervention and the UC arm, respectively. Although there were differences in the incidence of AEs between the treatment arms, the AE profile in the proactive intervention arm was consistent with previous safety experience for this medication.

Conclusions:

A proactive multifactorial risk factor intervention strategy that simultaneously treated both BP and cholesterol regardless of individual risk factors per se, is more effective in reducing calculated Framingham 10-year CHD risk than UC in patients with hypertension and additional risk factors.

Key words::

• Amlodipine
• Atorvastatin
• Cardiovascular risk
• Dyslipidemia
• Global risk
• Hypertension
• Usual care

Transparency

Declaration of funding

The study was funded by Pfizer Inc, which provided support with the study design; study drug; collection of data and maintenance of the study database. Statistical analyses were performed by S.S. of Pfizer Inc. S.S., M.W. and C.Y. of Pfizer Inc, also contributed towards discussions of the data analysis plan, interpretation of the results and support with writing the paper for publication.

Declaration of financial/other relationships

J.Z., S.E., A.P., J.-H.K. and A.Al-K. have served as consultants or received travel expenses, or payment for speaking at meetings, or funding for research from one or more pharmaceutical companies (including Pfizer who sponsored this study) that market blood-pressure-lowering or lipid-lowering drugs. M.W., C.Y. and S.S. are employees of Pfizer Inc. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgment

Editorial support was provided by Sarah Partridge, PhD, and Penny Gorringe, MSc, of UBC Scientific Solutions and funded by Pfizer Inc. Independent data safety monitoring was conducted by Nick Freemantle, PhD, John Hampton, MD, and Gorm Jensen, MD, DMSc.

The authors thank all investigators and co-investigators in the participating countries: Costa Rica: Roberto Gamboa-Garro, Javier Cespedes-Vargas, Catalina Sanchez-Soto, Javier Moya-Rodriguez, Linette Gonzalez-Rojas, Miguel Angel Jones-Chacon, Luis Carlos Ramirez, Alejandro Cob-Sanchez, Georgina Dengo-Sotela, Ignacio Gamboa Apestegui, Brigitte Sucaet, Claudio Slon-Hitti, Guiselle Mesen, Rodrigo Zumbado, Jaime Tortos-Guzman, Ann Echeverri-McCandless, Marcela Martinez-Elizondo, Mary Vinocour-Fornieri, Marisol Duran-Ramirez, Grace Yung-Li; Croatia: Dubravka Bokarica, Merim Bezdrov, Ines Car, Tatjana Cikac, Renata Cop, Brigita Haubrich Hrandek, Jadranka Javoric, Goran Kotur, Ksenija Kranjcevic, Goran Lazic, Zoran Maravic, Srecko Margetic, Lidija Primorac, Mladen Prlina, Nada Franic Smiciklas, Biserka Grilec, Mladen Stritof, Zrinka Bradicic Vivoda, Davorka Vrdoljak; Czech Republic: Petr Herle, Pavel Kos, Vladimir Marek, Zuzana Miskovska, Jan Miskovsky, Dana Moravcikova, Eliska Motlikova, Ivana Hanusova, Anna Nejedla, Bohumil Seifert, Adriana Youngova, Bohumil Skala, Michal Vecerek, Jitka Winklerova; Dominican Republic: Claudio Almonte, Ysmenia Diez, Elaine Nunez, Angel Gonzalez-Medina, Laiden Suarez-Fuster, Rafael Pichardo, Carmen Rodriguez, Ana Sanchez; Indonesia: Chandramin Chandradin, Ananda Wardoyo, Mei Lestari Harahap, Achyar Achyar, Dede Kusmana, Iwan Dakota, Basuni Radi, Antonia Anna Lukito, Edward Eddy, Lukman Hakim Makmun, Sally Aman Nasution, Erwan Martanto, Chaerul Achmad, Eko Antono, Sodiqur Rifqi, Susi Herminingsih, R. Mohammad Yogiarto, Djoko Sumantri, Agus Subagjo; Jordan: Ahnaf Albatayneh, Nidal Khatib, Zakaria Qaqa, Akram Al Saleh; Korea, Republic of: Sang-Hong Baek, Ju-Yeol Baek, Hae Ok Jung, Pum-Joon Kim, Mahn-Won Park, Seong Gyu Yoon, Seung-Yun Cho, Sang-Hak Lee, Sung Ha Park, Seung-Ho Hur, Yun-Kyeong Cho, Hyung-Seop Kim, Kwon-Bae Kim, Chang-Wook Nam, Myung Ho Jeong, Duk-Hyun Kang, Cheol Ho Kim, In-Ho Chae, Young-Seok Cho, Dong-Ju Choi, Kwang-Il Kim, Tae-Jin Youn, Dong-Soo Kim, Dae-Kyeong Kim, Seong-Man Kim, Tae-Hyun Yang, Kee-Sik Kim, Sung-Gug Chang, Ji-Yong Choi, Jin-Bae Lee, Young-Soo Lee, Jae-Kean Ryu, Moo-Hyun Kim, Kwang-Soo Cha, Kwang-Kon Koh, Hyuck Moon Kwon, Bum Kee Hong, Pil-Ki Min, Se-Joong Rim, Young Won Yoon, Seung-Hwan Lee, Jang-Young Kim, Mi Young Lee, Young Goo Shin, Byung-Su Yoo, Byung-Hee Oh, Hae-Young Lee, Jae-Hyeong Park, Jae-Hwan Lee, Seung Woo Park, Jidong Sung, Hong-Seog Seo, Eung Ju Kim, Wan-Joo Shim, Seong-Mi Park, Seung-Jea Tahk, Byoung-Joo Choi, So-Yeon Choi, Un-Jung Choi, Jung-Won Hwang, Soo-Jin Kang, Hong-Seok Lim, Joon-Han Shin, Sung-Il Woo, Myeong-Ho Yoon; Kuwait: Mousa Akbar, Plamen Petrovski, Khalid Yassin, Mohammed Zubaid, Amr Ali; Lebanon: Atika Adhami, Hamid El Bayeh, Salah Chouairi, Antoine Saadallah Sarkis; Malaysia: Aznida Firzah Abdul Aziz, Saharuddin Ahmad, Nor Asiah Hashim, Siew-Kim Kwa, Mastura Ismail, Wah-Yen Lee, Selvarajah Sathaya, Chandravathana Rajathurai, Gnanasegaran Xavier; Mexico: Ricardo Alvarado-Ruiz, Roxana Reyes-Sanchez, Paulina Sida-Perez, Ricardo Cabrera-Jardines, Ambrosio Cruz-Diaz, Francisco Javier Rangel-Rojo, Manuel Duarte-Vega, Luis Enrique Zamora-Angulo, Manuel Gonzalez-Ortiz, Karla P. Guerra-Guevara, Jose Antonio Robles, Maria Elizabeth Halley-Castillo, Carlos Aranza-Doniz, Heidy Marlene Archundia-Cabanez, Carlos de Jesus Lopez-Morales, David Perez-Moreno, Alejandra Meaney-Martinez, Ignacio Rodriguez-Briones, Erika Araida Delgado-Galicia; Panama: Suyin Quintero, Rita Trujillo, Carmen Guardia, Ycly Jaen; Philippines: Mary Anne Lim-Abrahan, Karla Kristine Silverio Fernando, Araceli Panelo, Jeimeen Agra, Felix Eduardo R. Punzalan, Mary Dawn Aquino-Nablo, Gabriel B. Jocson III, Elizabeth L. Roasa, Maren Garcia, Rody G. Sy, Philip U Chua, Efren R. Vicaldo; Russian Federation: Nadir M. Akhmedzhanov, Nadezhda Kachanova, Grigory P. Aroutyunov, Tatiana K. Chernyavskaya, Ekaterina B. Meskhidze, Boris Y. Bart, Marina P. Mikhailusova, Nadezhda K. Runikhina, Lyudmila P. Egorova, Drosida Maslakova, Yuliya A. Sychova, Yuri B. Karpov, Boris P. Garshin, Boris V. Kosenko, Elena N. Kurakova, Viktor A. Kostenko, Nikolay Bokovin, Farid Tumarov, Yuri M. Lopatin, Oleg V. Ilyukhin, Elena N. Zavodchikova, Valentin S. Moiseyev, Zhanna Kobalava, Elena P. Korovina, Anna Rubanova, Svetlana V. Villevalde, Alexander A. Petrov, Yuri V. Shubik, Irina Aparina, Zinaida Solovieva, Alexander Vishnevskiy, Leonid Bershtein, Dmitry V. Kositcyn, Elena N. Molotkova, Grigory B. Smirnov, Mikhail Terskikh, Aynar S. Yusupov, Yury S.Titkov, Lyudmila P. Zharkova, Irina V. Andreeva, Denis V. Ilyin, Konstantin N. Zrazhevsky, Zhanna V. Paltsman, Natalya A. Rodina; Taiwan: Jung-fu Chen, Ming-Chun Kuo, Zhih-Cherng Chen, Yu-Lin Ko, Wen-ter Lai, Kun-Tai Lee, Li-Jen Lin, Kwo-Chang Ueng, Chuen-den Tseng, Jiann-Shing Jeng, Yi-Chih Wang, Kuo-Yang Wang; Thailand: Surin Assawawitoontip, Thanavit Sakulsaengprapha, Kidaphol Wadhanakul, Puntudis Thongouppakarn; Turkey: Hakan Alp Bodur, Mehmet Tunca, Kerim Guler, Vakur Akkaya, Abdulbaki Kumbasar, Ismail Cengiz, Abdulkadir Ergen, Serap Sertkaya, Aysegul Zobi Akpolat, Mehmet Sonbahar, Ali Yildrim, Tufan Tukek, Mustafa Cakirca, Mehmet Ali Cikrikcioglu, Tulin Kurt, Neslihan Kurtulmus, Aydin Tunckale, Asli Curgunlu; United Arab Emirates: Bashar Afendi, Ali El Houni, Abdullah Al Naeemi, Azan Salim Bin Brek, Amna Feiruz, Ahmed Gabroun, Ghaida Kaddaha, Sameem Matto; Venezuela: Norka Antepara, Alvaro Jimenez, Gerardo Chazzim, Evelyn Martinez, Antonio Javier Delgado, Mirecly Guzman, Carlos Luis Delgado, Jose David Ribaldi.

This work was presented as a poster at the 20th Meeting of the European Society of Hypertension, Oslo, Norway on June 20, 2010.