Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Parving H-H, Brenner BM, McMurray JJV, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367: DOI: /NEJMoa

2 ALTITUDE Supplementary Material Acknowledgements... 2 Data Monitoring Committee Members... 2 National leaders... 2 ALTITUDE Investigator List... 2 Figure S1. Numbers of patients who were screened for the study, who underwent randomization, and who completed the study... 5 Figure S2. Relative risks for primary composite outcome in prespecified subgroups... 6 Figure S3. Changes from baseline in blood pressure, urinary albumin-to-creatinine ratio, estimated glomerular filtration rate, and serum potassium according to study group Table S1. Inclusion and exclusion criteria... 9 Table S2. Adjudication of endpoints Table S3. Treatment guidelines for hyperkalemia (serum K+ more than 5.0 mmol/l) Table S4. Endpoint data presented to the data monitoring committee (14th December 2011) DMC Recommendation Letter December 14 th Table S5. Additional baseline characteristics Table S6. Baseline medications Table S7. Concomitant medication during the study Table S8. Clinical endpoints by baseline potassium subgroup Table S9. Stroke-rates per 100 patient-years of follow-up per treatment arm in each trial Supplementary Methods Supplementary Adverse Event Information. Other relevant adverse events reported

3 Acknowledgements The authors want to acknowledge the contribution of the participating patients, Ilse Devrieze, Jürgen Armbrecht and Mathieu Ghadanfar from Novartis, members of the Data Monitoring Committe, National Leaders and all investigators. Data Monitoring Committee Members Giancarlo Viberti (Chair, UK), John M. Lachin (USA), Bernard Zinman (Canada), Terje R. Pedersen (Norway) National leaders A S Villamil, L Juncos (Argentina), R Prager (Austria), G Verpooten (Belgium), M T Zanella (Brazil), L Leiter (Canada), C Pan, H Wang (China), R Botero (Colombia), R Cifkova (Czech Republic), J Sandahl Christiansen (Denmark), P-H Groop (Finland), M Marre (France), H Haller, G Nickenig (Germany), K Siamopoulos (Greece), L Gero (Hungary), A Maggioni, G Remuzzi (Italy), S Shigenhiro Katayama (Japan), S-G Kim (Korea, Republic of), Z Petrulioniene (Lithuania), D Lok, A Kooy (Netherlands), R Jorde (Norway), F Medina (Peru), J Polonia (Portugal), K-S Wong (Singapore), A Dukat (Slovakia), B L Rayner (South Africa), L Ruilope (Spain), L Weiss (Sweden), R Wuethrich (Switzerland), W Sheu (Taiwan), P Sritara (Thailand), A Comlekci (Turkey), R Bilous (United Kingdom), R Toto, K Jamerson (United States), E Carillo (Venezuela) ALTITUDE Investigator List Argentina - Luis Juncos, Marcelo Orias, Emilio Kuschnir, Marcelo Rusculleda, Sergio Garcia, Eduardo Farias, Luis Lema, Miguel Hominal, Oscar Montaña, Jorgelina Sala, Monica Diaz, Daniel Piskorz, Nestor Vita, Leon Litwak, Isaac Sinay, Marcos Marin, Pablo Massari, Claudio Majul, Diego Aizemberg, Guillermo Moises Azize, Ines Bartolacci, Ana Reboredo, Marisa Vico, Ricardo Milesi, Horacio Sessa, Dr. Alfredo Wassermann, Fernando Margulis, Pedro Zangroniz Austria - B Watschinger, R Prager, H Toplak, B Paulweber, H Drexel, C Francesconi, B Foeger, G Mayer, R K-Braun, H Brath Belgium L V Gaal, PVD Niepen, A Persu, C Vercammen, AD Vriese, F Coucke, C Mathieu, F Fery, S Treille, G Meeus, KV Acker, A Scheen, J Tits, J Ruige, J-M Krzesinski, G Hollanders, F Liénart, P Dendale, M Quinonez, P Arnouts, J Vanuytsel Brazil - M Zanella, D Mion Jr, A Forti, F Almeida, R Cunha, RB de Paula, A Brandao, J Rocha, E Krieger, G Feitosa, J Saraiva, J Martin, MN Hissa, H Schmid, J Felicio, J Sgarbi, W Oigman Canada K Bowering, C Garceau, JC Berlingieri, SJ Weisnagel, P Hardin, C Powell, R Turcot, N Muirhead, R Aronson, YT Barima, AW Steele, S Pandey, V Woo, J Cha, D Dattani, C Godin, M Gupta, L Leiter, K Saunders, G Tellier, R Ting, S Tobe, G Chouinard, R Schlosser, H Khandwala, JM Ekoe, SB Harris, V Pichette, P Lachance, TC Ooi, H Tildesley, B Barrett, S Cournoyer China - J Lu, H Zhang, X Liu, S YAN, X Qi, Q Li, H Li, X Lv, J Yang, N Sun, W Xia, N Wang, N Tong, C Mei, S Gu, J Zhang, X Chen, L Li, B Su, L Wang, M Qiu, X Wu, Z Liu, W Jia, G Xu, J Dong, D Zhu, M Zhang, J Yan, B Liu, J Chen, J Fu, L YAN, X Zhan, L Zhong, T yang, J Ma, M Xu, X Xu, B Shi, Q Ji, H Zhong, R He, Z Yuan, Z Zhou, H Lin, W Yang, Y Ke, Q Li, T Hong Colombia - C Franco, L Casas, A Triana, R Botero, C Jaramillo, E Hernandez, C Barrera, D Blanco Czech Republic R Stipal, P Widimsky, L Dohnalova, M Komroskova, M Kvapil, J Belobradkova, V Tesar, R Cifkova, P Vodnansky, B Kocourkova Denmark - JS Christiansen, H-H Lervang, H Perrild, P Rossing, O Oestergaard, H Juhl, B Thorsteinsson, O Snorgaard, S Urhammer, K Egstrup Finland - T Tikkanen, K Helin, J Rinne, J Lahtela, J Strand, E Valtonen, M Saari, K Kananen, K Savela France - M Marre, J Blacher, J-C Aldigier, P Zaoui, J-P Fauvel, D Gouet, P-E Valensi, G Charpentier, R Marechaud, A Penfornis, M Ovize, AA-Kovalchuck 2

4 Germany H Haller, F Dellanna, N Schoen, W Groeschel, F Eickhoff, M Hanefeld, J Merke, M Rambausek, U Zimmermann, W Stuetz, A Vosskuehler, G Hevendehl, U Schax, G Lehmann, A Haack, J Hilgenberg, G Klausmann, V Adelberger, S Gessner, A Fiesselmann, E Oerter, T Hohenstatt, A Groeschel, T Behnke, RT-Sisting, D Schoch, T Bieler, S Schleyer, U Altes, C Klepzig, G Rudofsky, G Mueller, F Burkhardt, K Reschke, I Senftleber, CK-Wiesweg, H-J Herrmann, R Brandstetter, A Segner, G Nickenig, H Schmitt, R Rippert, R Goebel, F Schreibmueller, I Pencz, P Ott Greece K Siamopoulos, I Migdalis, S Pappas, E Pagkalos, A Yalouris, A Tsapas, E Maltezos, N Tentolouris, I Papadakis, G Ioannidis, D Goumenos Guatemala V Corona, R Gonzalez, F Haase, V Monterroso, V Sánchez, E Turcios, F Wyss, JL Arango Hungary - B Bako, L Deak, E Dömötör, M Dudas, T Fulop, I Kiss, L Koranyi, Z Lengyel, G Nyirati, T Oroszlan, S Aniko, P Vörös, J Kapocsi, I Wittmann, G Paragh, G Abraham India - N Tandon, N Thomas, V Mohan, R Sahay, B Sethi, V Rao, S Kumar, S Chowdhury, M Dharmalingam, V Seshiah, G Bantwal, V Viswanathan, C Yajnik, P Adhikari, U Krishnan, P Varthakavi, J Hiremath, A Bhattacharyya, S Dani, K K Modi Italy - N Glorioso, M Morosetti, F Veglio, F Perticone, F Dotta, F Quarello, G Sesti, A Aiello, A D'Ospina, C Giordano, S Novo, A Santoro, C Ferri, V Capuano, B Trimarco, G Tonolo, G Villa, A De Pellegrin, G Zanette, M Federici, G Aucello, P Piatti, A Vinciguerra, E Mannarino, S Taddei, S Filetti, G Grandaliano, N Marchionni, C Lambiase, F Locatelli, F Scanferla, G Lembo, S Leotta, L Mos, P Calatola, R Fogari, S David, R Pedrinelli, A M Pignone, D Cozzolino, M T Bevilacqua, C Catena, S Del Prato, G Cerasola, S Frontoni, C Falcone, A Porta, E Bonora, R Cocchi, A Fucili, A Frisinghelli, M Volpe, S Carugo, S Gambardella, V Spagnuolo, G Maglia, A R D'Angelo, A Corsi, P P Limone, A Guarnieri, E Ghigo, E Ronchi, M Ravera, G A Scioli Japan - M Sekiguchi, S Aoki, Y Ogawa, H Seino, Y Onishi, A Tojo, M Narimiya, Y Iwaita, H Takeda, H Shimizu, T Yamada, S Kojima, S Zushi, S Kaneko, A Matsumoto, S Kajiyama, H Fujita, K Shikata, A Tone, S Matsubayashi, S Tanaka, T Sekigami, Y Tatsukawa, N Abe, K Kawahara, H Kasahara, Y Maeda, Y Suzuki, H Okamoto, K Tachi, K Yamada, T Uzu, T Itou, T Fukui Korea, Republic of - S Kim, Y Kim, W Cho, I Kwak, D Chae, H Oh, S Ha, Y Shin, D Cha, Y Kim, S Kim, S Kang, C Lim, J Song, Y Kwon Lithuania J Badariene, I P-Labutiniene, L Zabuliene, V Poteliuniene, M Miglinas Netherlands - A. Kooy, A.H. van den Meiracker, P.J.H. Smak Gregoor, A.J. Luik, B.J. Potter van Loon, H.J. Feenstra, H.A.H. Kaasjager, P.P. Viergever, A.J.J. Woittiez, T. van Bemmel, A.G. Lieverse, S. Simsek, C.A.J.M. Gaillard, C. van der Zwaan, Dirk J.A. Lok, Wilco Spiering, P.R. Nierop, M.G.A. Baggen, R.J.M. Leendert, A. de Jong, P.B. Leurs, H.H. Vincent, E.H.R. Wins, A.A. Voors, E. Ronner, J.E. Heeg, J.M.C. van Hal, Ton Boermans, W.L. Feis, G. Mostard, R.C. Bakker, P.H.J.M. Dunselman Norway - R Jorde, S Skeie, H Istad, G Skjelvan, J Gronert, T Tomala, S Gudnason, D Tarje Torvik, K Risberg, S Abedini Peru - W Cabrera, B Medina, F Medina, B Herrada, A Saavedra Portugal - D Jorge Polonia, D Luis Providencia, D Carvalho, M P Vasconcelos, G F da Silva, P Branco, D V Gil, A G da Costa, P M da Silva, L Arez, L Martins, R Birne Slovakia J Dzuponova, M Surovcikova, J Culak, A Dukat, S Filipova, I Andre, J Stevlik, R Uhliar, L Fabryova, J Benacka, D Koleny, M Szentivanyi, V Spisak, D Pella, E Pastrnakova, E Martinka Singapore - T Chua, K S Wong, T Lau, T G Ng, L Y Yeoh South Africa - S A. Bhana, B Rayner, H Wellmann, A Amod, N Ranjith, F Ahmed, P Rheeder, H Makan, P Naicker, G Podgorski Spain - E De Teresa, J Olivan, V L Fernandez, S T Povedano, M Terns, W Ricart, J M Gonzalez, P Fernandez, L de Teresa Parreño, J Redon, J Parra, C Calvo, I Lopez, J G Puig, A Calle, J C F Garcia, J M Lopez, M L Jimenez, B Fraile, J S Perez, J J Nadal, E Guija, J Calviño, V Barrios, J N Iglesias, P Armario, M Garcia, P Aranda, C Brotons, L Ruilope, P Gomez, A M Catelao, A R Cusachs, M Sarro, V Martinez, M H dell Valle, F Trias, A Comas, N Salvador, F Martinez, F Hernandez, J Martinez, C Mateos, J L Peral, J Tolosana, J Sobrino, J Isart, J Vizcaino, F Fernandez Vega, J L Zamorano, M Bacariza, A Soubriet, A Fernández-Cruz, R Querejeta, V Muñoz Leira, F E Calvo Iglesias, O Ibrik, D Martin, M S Nanclares, J D Mediavilla, J M Galceran, A Lopez, T Muros, J Pascual, F Casalla, F Tornero, G Fernandez Sweden - L Weiss, P Pettersson, H Olsen, F Franke, U Stroembom, H Furuland, H Larnefelt Switzerland - Y Allemann, R Krapf, R Wuethrich, P Gerber, R Munger, D Hayoz, H.J. Graf, M Burnier, A Petrillo, R Batt, E N-Constam, T Moccetti, T Bianda, H Rickli, C Bulliard Taiwan - Kwan-Dun Wu, Shih-Hua Lin, Chih-Jen Wu, W Huey-Herng Sheu, Shih-Li Su, Shih-Chueh Chen, Chien-Wen Chou, Chien-Te Lee, Te-Cheng Yang, Hung-Chun Chen 3

5 Thailand - P Sritara, A Sukonthasarn, C Sriratanasathavorn, S Eiam-Ong, O Supasyndh, T Chanchairujira, C Kitiyakara Turkey - A Comlekci, M Arici, C Usalan, S Guneri, M Koc, B Kalender, K Ates, C Gurgun, M Araz, B Demirbas United Kingdom - W Biernacki, J Calvert, P Eavis, J Kerrane, J Litchfield, A Middleton, J Roberts, H Simpson, H Charles, A Jardine, M Fisher, D Banerjee, I Gallen, L Gnudi, J Harvey, P O'Hare, J Vora, P Winocour, H Soran, D Browne, D Darko Venezuela - J G Mancebo, E R de Roa, N Antepara, E Carrillo, M Berrizbeitia, L Guevara, N Pernalete, C Ontiveros United States W Zigrang, Eric Blakney, P Rosenblit, R Weinstein, L Klaff, R Lipetz, E Busick, P Tung, M Cooperman, S Michael, C-Huan Sun, T Hart, A Maddux, R Bowden, C East, R Arakaki, B Villafuerte, Z Mamish, R Mendez, L Connery, K Nour, A Wynne, R Busch, B Zamora, R Sachson, J Prasad, G Lasala, M Smith, D Fitz-Patrick, L Ruiz-Rivera, E Barranco, R Solomon, A Woolley, C Brown, Z Freedman, S Schmidt, J Pollock, M Ruddy, R Toto, N P. Kopyt, A Bazzi, B Horowitz, W Feng, T Wahl, D Duprez, J Gilbert, S Steigerwalt, J Jacqmein, S Gorton, J Allison, III, J Pino, J Lock, W Leimbach, J Anderson, M Beacom, W Craig, D Gorson, H Kerstein, S Segal, H Downey, G Ledger, J McGill, J Gabriel, T Nolen, L Levinson, T Williams, D Levenson, S Lerman, C Minehart, N Agarwal, Sl Verma, M Valitutto, K Demetry, J Mersey, D Koeper, P Fanti, G Eng, K Jamerson, R Grimm, T Fagan, M Bajaj, L Katz, G Portnay, A Altschuller, V Desai, S Bilazarian, E Ipp, R Rodelas, D Burstein, J Berg, J Velez, R Lund, A Rekhi, E Martin, J Martin, D Robertson, N Singh, P Narayan, M Moustafa, D Lanier, M Seidner, A Phillips, B Vaughters, A Sprague, S Swartz, R Lopez, J Kumar, P Bressler, L Sadler, J Wise, A Kilbane 4

6 Figure S1. Numbers of patients who were screened for the study, who underwent randomization, and who completed the study. Some patients were excluded for more than one reason. 21,157 patients screened 12,551 Were excluded 345 Unacceptable past medical history / concomitant diagnosis 244 Intercurrent medical event 5,943 Unacceptable laboratory value 475 Unacceptable test procedure result 5,036 Did not meet diagnostic / severity criteria 190 Unacceptable use of excluded medications / therapies 921 Subject withdrew consent 24 Unknown 767 Other 8,606 patients randomized 45 Were Excluded 23 GCP violation 22 Mis-randomized 8,561 patients analyzed (study closure date 31 Jan 2012 Aliskiren n = 4,274 Placebo n = 4,287 Alive n = 3,775 Dead n = 376 Vital status unknown n = 123 Alive n = 3,830 Dead n = 358 Vital status unknown n = 99 5

7 Figure S2. Relative risks for primary composite outcome in prespecified subgroups. Shown are the comparisons between the aliskiren group and the placebo group. The sizes of the squares are equal and not proportional to event numbers 6

8 7

9 Figure S3. Changes from baseline in blood pressure, urinary albumin-to-creatinine ratio, estimated glomerular filtration rate, and serum potassium according to study group. Mean blood pressure measured while the patients were seated (Panel A). Change in geometric mean with 95% confidence intervals is shown for the ratio of urinary albumin-to-creatinine (Panel B). Estimated glomerular filtration rate (Panel C) and serum potassium (Panel D). Panels A, C and D are shown with SE bars. Solid line indicate aliskiren, dotted line placebo. A 144 B 1.2 Systolic/Diastolic BP (mmhg) Ratio of geometric means of urinary albumin:creatinine ratio C Time Period (months) 58 D Time Period (months) 4.70 egfr (ml/min/1.73m 2 ) Time Period (months) Serum potassium (mmol/l) Time Period (months) 8

10 Table S1. Inclusion and exclusion criteria Inclusion criteria For Visit 1 Patients with type 2 diabetes mellitus who are on oral antidiabetics and/or insulin or documented fasting plasma glucose 7.0 mmol/l or 2-h plasma glucose 11.1 mmol/l Male or female patients 35 years of age Additional criteria for Visit 3 Patients who provide written informed consent Patient on conventional therapy (national guidelines) and on concomitant ACEI or an ARB without any adjustments to the antihypertensive therapy for at least four weeks prior to randomization. At least one of the following: o Persistent macroalbuminuria (UACR 200 mg/g * ) and egfr 30 ml/min/1.73 m 2 o Persistent microalbuminuria (UACR 20 mg/g and <200 mg/g * ) and a mean egfr 30 and <60 ml/min/1.73 m 2 o A history of cardiovascular disease (e.g. myocardial infarction, stroke, heart failure or coronary artery disease) and a mean egfr 30 and <60 ml/min/1.73 m 2 Exclusion criteria For patients with any of the following at Visit 1 through Visit 3 General criteria Serum potassium >5.0 mmol/l directly preceding Visit 3 Type 1 diabetes mellitus Unstable serum creatinine ** Cardiovascular Congestive heart failure NYHA class III or IV history Stroke, transient ischemic cerebral attack, MI, unstable angina, CABG, PCI, hospitalization due to HF, 3 months prior to visit 1 Hypertension at Visit 3 with mssbp 170 mmhg or msdbp 110 mmhg Hypertension at Visit 3 with mssbp 135 and <170 mmhg or msdbp 85 and <110 mmhg unless treated with at least three antihypertensives Second or 3 rd degree heart block without a pacemaker or life threatening or uncontrolled arrhythmia or clinically significant valvular heart disease Renal artery stenosis Surgical or medical History of malignancy within the past five years condition Concurrent life threatening condition with a life expectancy less than 2 years. Patients with previous renal transplant or under immunosuppressive therapy. Any surgical or medical condition that alters the pharmacokinetic parameters of the study drug, or jeopardizes the evaluation of efficacy or safety of the study drug or affects patient s compliance A history or evidence of drug or alcohol abuse within the last 12 months Hypersensitivity or allergy or suspected/known contraindications to the study drugs Pregnant (confirmed by a positive hcg test), lactating women or women of child-bearing potential. Others Concomitant treatment with > 2 agents blocking the renin-angiotensinaldosterone system. Potassium-sparing diuretics. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer Persons directly involved in the execution of this protocol. Patients enrolled in the CSPP100AC2201 trial. Noncompliance to medical regimens or unwillingness to comply with the study protocol * In at least 2 out of 3 morning voided urine samples ** Defined as 20% difference between two consecutive serum creatinine measurements before Visit 3 mssbp, mean sitting systolic blood pressure; msdbp, mean sitting diastolic blood pressure; MI, myocardial infarction; CAD, coronary arterial disease; HF, heart failure; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; hcg, human chorionic gonadotropin, UACR, urinary albumin to creatinin ratio, egfr, estimated glomerular filtration rate 9

11 Table S2. Adjudication of endpoints. Death Myocardial Infarction Unplanned Hospitalization for Heart Failure End Stage Renal Disease Renal death Doubling of Baseline Serum Creatinine Concentration Resuscitated Sudden Death Non-Fatal Stroke Cardiovascular Noncardiovascular Unknown Non-procedural Cardiovascular cause, including sudden death, death during a cardiovascular procedure or as a result of procedure-related complications, presumed sudden and presumed cardiovascular death, or death resulting from a documented cardiovascular cause other than those listed above With an unequivocal and documented noncardiovascular primary cause of death Insufficient data is available to make an reasonable differentiation of cardiovascular or non-cardiovascular cause of death Troponin or CKMB > 2 x URL AND either Ischemic symptoms OR new ischemic ECG changes Troponin or CKMB > 3 x URL/ Troponin or CKMB > 5 x URL Post-PCI/Post- Cardiac surgery Presentation to an acute care facility requiring an overnight hospitalization with an unexpected exacerbation of heart failure (1 or > symptoms AND 2 or > signs), required treatment with either IV diuretics, vasodilators, inotropes, mechanical fluid removal, or insertion of an intra-aortic balloon pump for hemodynamic compromise, initiation of standing oral diuretics or intensification of the maintenance diuretic. Initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0mg/dL Death attributable to kidney failure, need for renal replacement therapy with no dialysis or transplantation available or applied. A doubling of baseline serum creatinine to a value greater than the upper limit of normal as determined by 2 central laboratory measurements separated by > 30 days. Subject experiences sudden death or cardiac arrest and is successfully resuscitated by cardioversion, defibrillation or cardiopulmonary resuscitation with a meaningful recovery of consciousness. A focal neurological deficit of central origin lasting > 24 hours, with or without imaging confirmation of cerebral infarction or intracerebral hemorrhage or other presentation meeting ALTITUDE criteria. Further classified as: ischemic, ischemic with hemorrhagic conversion, primary intracranial hemorrhage, unknown 10

12 Table S3. Treatment guidelines for hyperkalemia (serum K+ more than 5.0 mmol/l) General principles Any patient with a serum K+ > 5.0 mmol/l (meq/l) following randomization (Visit 3) requires regular, repeated, checks of potassium concentration (beyond that prescribed in the protocol) until it is clear that the potassium concentration is stable and not rising into the range of concern ( 5.5 and < 6.0 mmol/l) or potential danger ( 6.0 mmol/l). Investigators should discontinue study drug, temporarily, in any patient with a serum K+ 5.5 mmol/l following randomization (Visit 3) and follow the other measures outlined below. Corrective action for management of hyperkalemia K+ > 5.0 and < 5.5 mmol/l Confirm potassium concentration in a non-hemolyzed sample Reinforce low potassium diet and restriction of food/drinks with high potassium content (e.g. orange juice, melon, bananas, low-salt substitutes etc.) Review medical regimen (including dietary supplements and over-the-counter medications) for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of these agents, only if clinically acceptable: Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination products with thiazide or loop diuretics remember that potassium-sparing diuretics are excluded per protocol Potassium supplements e.g. potassium chloride Non-steroidal anti-inflammatory drugs (NSAIDs) Cyclo-oxygenase-2 (COX-2) inhibitors Trimethoprim and trimethoprim-containing combination products such as trimethoprim/sulfamethoxazole Mineralocorticoid receptor antagonists e.g. spironolactone and eplerenone (do not discontinue in patients with prior myocardial infarction or heart failure) remember that these drugs are excluded per protocol Herbal Supplements 11

13 For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian ginseng, hawthorn berries Repeat K+ measurement within 5 days If K+ remains > 5.0 and < 5.5, regularly monitor K+ levels to ensure stability (suggested once monthly) K+ 5.5 and < 6.0 mmol/l Confirm potassium concentration in a non-hemolyzed sample Temporarily discontinue study drug Apply all measures outlined for K+> 5.0 and < 5.5 Repeat K+ measurement after 2-3 days If K+ < 5.5, consider resumption of study drug at lower dose with repeat potassium within 5 days K+ 6.0 mmol/l Immediately discontinue study drug Confirm potassium concentration in a non-hemolyzed sample Urgently evaluate patient and treat hyperkalemia as clinically indicated Apply all measures outlined for K+ > 5.0 and < 6.0 mmol/l No resumption of study drug without individualized case discussion with and permission from Novartis medical monitor 12

14 Table S4. Endpoint data presented to the data monitoring committee (14th December 2011) Aliskiren (N = 4283) n (%) Placebo (N = 4296) n (%) HR 95% CI P-value Variable Primary composite outcome 581 (13.6) 542 (12.6) 1.09 (0.97,1.22) Secondary composite outcome - CV 444 (10.4) 396 (9.2) 1.14 (0.99,1.30) Secondary composite outcome - renal 166 (3.9) 180 (4.2) 0.93 (0.76,1.15) Component event CV death 179 (4.2) 162 (3.8) 1.12 (0.90,1.38) Resuscitated sudden death 13 (0.3) 8 (0.2) 1.64 (0.68,3.95) Non-fatal MI 90 (2.1) 88 (2.0) 1.03 (0.77,1.39) Non-fatal stroke 112 (2.6) 85 (2.0) 1.34 (1.01,1.77) Unplanned hospitalization for heart failure 150 (3.5) 155 (3.6) 0.98 (0.78,1.23) Onset of ESRD/renal death 72 (1.7) 60 (1.4) 1.22 (0.87,1.72) Doubling of baseline serum creatinine 141 (3.3) 159 (3.7) 0.90 (0.71,1.12) Death from any cause 297 (6.9) 277 (6.4) 1.08 (0.92,1.27)

15 DMC Recommendation Letter December 14 th 2011 Unit for Metabolic Medicine Cardiovascular Division King s College London School of Medicine HODGKIN BUILDING ROOM 2.90W GUY S HOSPITAL LONDON SE1 9RT Tel/Fax: (0) Giancarlo Viberti MD FRCP Emeritus Professor of Diabetes & Metabolic Medicine 14 Dec 2011 Prof Hans-Henrik Parving MD, DMSc Executive Committee CHAIR (hhparving@dadlnet.dk) Department of Medical Endocrinology Rigshospitalet, University Hospital of Copenhagen Blegdamsvej 9 DK 2100 Copenhagen Denmark Prof Marc A Pfeffer MD, PhD Executive Committee CO-CHAIR (mpfeffer@rics.bwh.harvard.edu) Department of Medicine Brigham and Women s Hospital 75 Francis Street Boston, MA 02115, USA Re: ALTITUDE Data Monitoring Committee face-to-face meeting, 14 Dec 2011 Dear Drs. Parving and Pfeffer: The Data Monitoring Committee met on 14 December 2011 to review the second interim efficacy analysis, and the accumulated data related to adverse events, laboratory values and physical status. A total of 1123 adjudicated primary outcome events were tabulated, 581 (13.6%) treated with aliskiren versus 542 (12.6%) with placebo. The hazard ratio was a 1.09 increased risk with aliskiren with 95% confidence interval (0.97, 1.22), p = 0.17, 2-sided. This constitutes 69% of the projected total primary outcome events to be accrued. Even under the original design assumption of a 15% risk reduction (HR = 0.85), the conditional probability that the study would demonstrate benefit at the end of the trial is < The hazard ratio for the secondary cardiovascular outcome is 1.14 (95% CI: 0.99, 1.30), again suggesting harm. The hazard ratio for the non-fatal stroke component of the primary outcome is 1.34, 95% CI (1.01, 1.77), 112 (2.6%) vs. 85 (2.0%), p = The hazard ratio for the secondary renal outcome is 0.93 (CI: 0.76, 1.15), suggesting some potential for minimal renal benefit. However, this benefit is manifest in a slightly lower incidence of doubling of serum creatinine (141 versus 159), not ESRD or renal death (72 versus 60). In fact there is an increase in other indices of renal impairment, 14

16 and there are other statistically significant and clinically compelling increased risks with aliskiren in this high risk population. Specifically: There is an excess of Serious Adverse Events of renal concern (i.e. renal impairment, renal failure acute, renal failure chronic, renal failure): 201 (4.7%) vs. 142 (3.3%) which is highly statistically significant, p = There is an increase in the incidence of SAEs of renal concern within each level of severity as assessed independently in a blinded fashion by Prof. Ritz (approximately 50% increase with aliskiren). There is an excess of Cerebrovascular Accident Serious Adverse Events with aliskiren: 85 (2.0%) vs. 58 (1.4%), p = There is an excess of Serious Adverse Events of Hyperkalaemia with aliskiren: 46 (1.1%) vs. 14 (0.3%), p < There is an excess of Adverse Events (including non-serious) of Hypotension with aliskiren: 494 (11.5%) vs. 319 (7.4%). There is an excess of Serious Adverse Events of Fall with aliskiren: 21 (0.5%) vs. 8 (0.2%), p = Deaths are slightly trending in the harmful direction: 307 (7.2%) vs. 289 (6.7%). There is an excess incidence of Creatinine > umol/l with aliskiren: 1244 (29.3%) vs (27.0%), p = There is an excess incidence of Creatinine > 50% increase from baseline with aliskiren: 1016 (23.9%) vs. 900 (21.1%), p = Consistently, there is an excess of emergent low values of egfr of 273 (6.6%) vs. 224 (5.4%), p = Lab results and vital signs are consistent with renin inhibition, both continuous and categorical, but without consequent improvement in patient outcomes Given these substantial safety concerns, the Data Monitoring Committee unanimously recommends that that all subjects should cease treatment with aliskiren in an orderly manner. Yours sincerely, Giancarlo Viberti MD FRCP Chairman Data Monitoring Committee ALTITUDE Study 15

17 Table S5. Additional baseline characteristics. Aliskiren Placebo Race no. (%) Caucasian 2419 (56.6) 2431 (56.7) Black 127 (3.0) 150 (3.5) Asian 1354 (31.7) 1360 (31.7) Other 361 (8.4) 335 (7.8) History of cardiovascular disease no. (%) Myocardial infarction 711 (16.6) 713 (16.6) Unstable angina pectoris 427 (10.0) 389 (9.1) Angina pectoris 415 (9.7) 444 (10.4) Percutaneous coronary intervention 592 (13.9) 625 (14.6) Coronary artery bypass grafting 530 (12.4) 527 (12.3) Stroke 438 (10.2) 409 (9.5) Transient ischemic attack 177 (4.1) 173 (4.0) Atrial fibrillation 380 (8.9) 351 (8.2) Heart failure 449 (10.5) 423 (9.9) Diabetes history no. (%) Duration of diabetes 1 yr 143 (3.3) 144 (3.4) > 1-5 yr 612 (14.3) 609 (14.2) > 5 yr 3519 (82.3) 3534 (82.4) Retinopathy 1586 (37.1) 1575 (36.7) Laser eye treatment 766 (48.4) 692 (44.0) Peripheral neuropathy 1183 (27.7) 1213 (28.2) Amputation of toe, foot or leg 174 (4.1) 165 (3.8) 16

18 Amputation above ankle: aliskiren n=45, placebo n=40. No significant difference was demonstrated for any of the variables listed, except for laser treatment; P=

19 Table S6. Baseline medications Medication no. (%) Aliskiren Placebo ACE inhibitor 1926 (45.1) 1866 (43.5) Angiotensin receptor blocker 2353 (55.1) 2434 (56.8) Loop-diuretics 1195 (28.0) 1257 (29.3) Thiazide diuretics 1705 (39.9) 1715 (40.0) Beta blocker 2150 (50.3) 2136 (49.8) Calcium channel blocker 2637 (61.7) 2624 (61.2) Statin 2726 (63.8) 2850 (66.5) Other lipid-lowering drug 697 (16.3) 661 (15.4) Antiplatelet drug 2678 (62.7) 2688 (62.7) Insulin 2437 (57.0) 2413 (56.3) Biguanide 1990 (46.6) 1967 (45.9) Sulfonylurea 1361 (31.9) 1373 (32.0) Thiazolidinedione 350 (8.2) 373 (8.7) No significant difference was demonstrated for any of the variables listed, except for statin use, P<

20 Table S7. Concomitant medication during the study. Medication Visit Concomitant therapy by visit Aliskiren (N=4272) Placebo (N=4285) Total (N=8557) ACE Inhibitor Visit 3 (baseline) Medication taken? N Yes 1925 ( 45.1%) 1864 ( 43.5%) 3789 ( 44.3%) No 2347 ( 54.9%) 2421 ( 56.5%) 4768 ( 55.7%) Visit 11 (month 12) Medication taken? N Yes 1647 ( 41.6%) 1604 ( 40.2%) 3251 ( 40.9%) No 2311 ( 58.4%) 2388 ( 59.8%) 4699 ( 59.1%) Missing Visit 15 (month 24) Medication taken? N Yes 1180 ( 38.2%) 1231 ( 39.0%) 2411 ( 38.6%) No 1909 ( 61.8%) 1922 ( 61.0%) 3831 ( 61.4%) Missing Angiotensin Receptor Blocker Visit 19 (month 36) Medication taken? N Yes 557 ( 37.9%) 575 ( 38.1%) 1132 ( 38.0%) No 913 ( 62.1%) 933 ( 61.9%) 1846 ( 62.0%) Missing Visit 3 (baseline) Medication taken? N Yes 2352 ( 55.1%) 2434 ( 56.8%) 4786 ( 55.9%) No 1920 ( 44.9%) 1851 ( 43.2%) 3771 ( 44.1%) 19

21 Medication Visit Concomitant therapy by visit Aliskiren (N=4272) Placebo (N=4285) Total (N=8557) Visit 11 (month 12) Medication taken? N Yes 2178 ( 55.0%) 2261 ( 56.7%) 4439 ( 55.8%) No 1782 ( 45.0%) 1730 ( 43.3%) 3512 ( 44.2%) Missing Visit 15 (month 24) Medication taken? N Yes 1740 ( 56.3%) 1785 ( 56.6%) 3525 ( 56.5%) No 1348 ( 43.7%) 1367 ( 43.4%) 2715 ( 43.5%) Missing Visit 19 (month 36) Medication taken? N Yes 778 ( 52.9%) 854 ( 56.7%) 1632 ( 54.8%) No 692 ( 47.1%) 653 ( 43.3%) 1345 ( 45.2%) Missing Beta blocker Visit 3 (baseline) Medication taken? N Yes 2150 ( 50.3%) 2135 ( 49.8%) 4285 ( 50.1%) No 2122 ( 49.7%) 2150 ( 50.2%) 4272 ( 49.9%) Visit 11 (month 12) Medication taken? N Yes 1994 ( 50.4%) 2033 ( 50.9%) 4027 ( 50.6%) No 1965 ( 49.6%) 1959 ( 49.1%) 3924 ( 49.4%) Missing Visit 15 (month 24) Medication taken? N Yes 1575 ( 51.0%) 1639 ( 52.0%) 3214 ( 51.5%) No 1514 ( 49.0%) 1514 ( 48.0%) 3028 ( 48.5%) Missing

22 Medication Visit Concomitant therapy by visit Aliskiren (N=4272) Placebo (N=4285) Total (N=8557) Visit 19 (month 36) Medication taken? N Yes 767 ( 52.2%) 790 ( 52.5%) 1557 ( 52.3%) No 703 ( 47.8%) 716 ( 47.5%) 1419 ( 47.7%) Missing Calcium channel blockers Visit 3 (baseline) Medication taken? N Yes 2630 ( 61.6%) 2619 ( 61.1%) 5249 ( 61.3%) No 1642 ( 38.4%) 1666 ( 38.9%) 3308 ( 38.7%) Visit 11 (month 12) Medication taken? N Yes 2371 ( 59.9%) 2425 ( 60.8%) 4796 ( 60.3%) No 1589 ( 40.1%) 1566 ( 39.2%) 3155 ( 39.7%) Missing Visit 15 (month 24) Medication taken? N Yes 1860 ( 60.2%) 1905 ( 60.4%) 3765 ( 60.3%) No 1228 ( 39.8%) 1247 ( 39.6%) 2475 ( 39.7%) Missing Visit 19 (month 36) Medication taken? N Yes 864 ( 58.8%) 922 ( 61.2%) 1786 ( 60.0%) No 606 ( 41.2%) 585 ( 38.8%) 1191 ( 40.0%) Missing Loop-diuretics Visit 3 (baseline) Medication taken? N Yes 1195 ( 28.0%) 1257 ( 29.3%) 2452 ( 28.7%) No 3077 ( 72.0%) 3028 ( 70.7%) 6105 ( 71.3%) 21

23 Medication Visit Concomitant therapy by visit Aliskiren (N=4272) Placebo (N=4285) Total (N=8557) Visit 11 (month 12) Medication taken? N Yes 1261 ( 31.8%) 1319 ( 33.0%) 2580 ( 32.4%) No 2699 ( 68.2%) 2673 ( 67.0%) 5372 ( 67.6%) Missing Visit 15 (month 24) Medication taken? N Yes 1064 ( 34.5%) 1114 ( 35.3%) 2178 ( 34.9%) No 2024 ( 65.5%) 2038 ( 64.7%) 4062 ( 65.1%) Missing Visit 19 (month 36) Medication taken? N Yes 547 ( 37.2%) 576 ( 38.2%) 1123 ( 37.7%) No 922 ( 62.8%) 930 ( 61.8%) 1852 ( 62.3%) Missing Thiazide diuretics Visit 3 (baseline) Medication taken? N Yes 1705 ( 39.9%) 1715 ( 40.0%) 3420 ( 40.0%) No 2567 ( 60.1%) 2570 ( 60.0%) 5137 ( 60.0%) Visit 11 (month 12) Medication taken? N Yes 1521 ( 38.5%) 1543 ( 38.7%) 3064 ( 38.6%) No 2434 ( 61.5%) 2444 ( 61.3%) 4878 ( 61.4%) Missing Visit 15 (month 24) Medication taken? N Yes 1133 ( 36.8%) 1138 ( 36.2%) 2271 ( 36.5%) No 1948 ( 63.2%) 2007 ( 63.8%) 3955 ( 63.5%) Missing

24 Medication Visit Concomitant therapy by visit Aliskiren (N=4272) Placebo (N=4285) Total (N=8557) Visit 19 (month 36) Medication taken? N Yes 552 ( 37.6%) 549 ( 36.6%) 1101 ( 37.1%) No 917 ( 62.4%) 953 ( 63.4%) 1870 ( 62.9%) Missing

25 Table S8. Clinical endpoints by baseline potassium subgroup Endpoints by potassium < 5.0 and 5.0 mmol/l and treatment Outcome Potassium < 5.0 mmol/l Potassium 5.0 mmol/l Aliskiren Placebo Hazard Ratio P value Aliskiren Placebo Hazard Ratio P value Interaction (N=3590) (N=3672) (95% CI) (N=682) (N=615) (95% CI) P value no. of patients (%) no. of patients (%) Primary Outcome 641 (17.9) 640 (17.4) 1.03 (0.92,1.14) (20.8) 92 (15.0) 1.48 (1.14,1.92) * Death from cardiovascular 196 (5.5) 186 (5.1) 1.08 (0.88, 1.32) (7.3) 29 (4.7) 1.62 (1.02, 2.55) causes Resuscitation after cardiac 16 (0.4) 7 (0.2) 2.33 (0.96,5.66) (0.4) 1 (0.2) 2.78 (0.29,26.70) arrest Myocardial infarction 113 (3.1) 126 (3.4) 0.91 (0.71,1.18) (5.0) 16 (2.6) 2.02 (1.11,3.66) * (fatal/non-fatal) Stroke (fatal/non-fatal) 123 (3.4) 110 (3.0) 1.15 (0.89,1.48) (3.5) 12 (2.0) 1.83 (0.91,3.65) Unplanned hospitalization 172 (4.8) 191 (5.2) 0.92 (0.75,1.13) (4.8) 28 (4.6) 1.09 (0.66,1.81) for heart failure ESRD* or death from renal 96 (2.7) 96 (2.6) 1.02 (0.77,1.35) (3.7) 17 (2.8) 1.41 (0.76,2.61) causes 24

26 Doubling of serum 170 (4.7) 189 (5.1) 0.91 (0.74, 1.12) (5.9) 28 (4.6) 1.37 (0.84,2.21) creatinine from baseline Cardiovascular composite 486 (13.5) 473 (12.9) 1.05 (0.93,1.19) (15.2) 66 (10.7) 1.49 (1.09,2.02) * outcome Renal composite outcome 207 (5.8) 219 (6.0) 0.96 (0.79,1.16) (7.3) 32 (5.2) 1.49 (0.96,2.33) * Death from any cause 303 (8.4) 308 (8.4) 1.01 (0.86,1.18) (10.7) 50 (8.1) 1.36 (0.95,1.95) * ESRD denotes end-stage renal disease. A patient may have had multiple cardiovascular and renal events of different types. The primary composite endpoint reflects only the first occurrence of any of the components. * P

27 Table S9. Stroke-rates per 100 patient-years of follow-up per treatment arm in each trial. Single RAAS blockade Dual RAAS blockade ONTARGET VALIANT 2 Captopril: Valsartan: CHARM Added ALTITUDE Data presented at ESC Unpublished data from the investigators 3. Data in press. 26

28 Supplementary Methods Run-in, randomization and follow-up Potentially eligible patients provided written informed consent and entered a four to 12-week screening period in which full eligibility criteria for randomization, including confirmation blood and urine tests, were evaluated (CONSORT diagram in Supplementary Figure S1). Laboratory values used for exclusion criteria were obtained in the screening period. This explains why patients at baseline could have a serum potassium above 5 mmol per Litre or estimated glomerular filtration rate below 30 ml per minute per 1.73m 2. Patients were stabilized on optimal therapy according to local guidelines including ACEi or an ARB, but not both. The randomization list was computer generated by a validated system that automated the random assignment of treatments groups to randomization numbers. Patients received aliskiren 150 mg or placebo on top of their conventional treatment, with forced uptitration to 300 mg once daily four weeks post randomization. Dose was only increased if no safety concerns. Baseline investigations at randomization included a questionnaire, physical examination including blood pressure, and measurement of glycated hemoglobin, potassium and lipids and urine albumin-to-creatinine ratio, as well as calculation of egfr. Follow-up visits occurred at 5, 8, 12 weeks after randomization, and then every three months. Physical examination and laboratory assessments were repeated at the 12 week visit and thereafter, adverse events, including information on endpoints were collected at each visit. If patients stopped medication or dropped out, attempts were made to keep the patient in the trial, by offering outpatient visits or regular telephone contacts. Between October 2007 and June 2010, 21,157 patients were screened, and 8606 randomised. 27

29 Supplementary Adverse Event Information. Other relevant adverse events reported. Blood creatinine increased 72 aliskiren, 57 placebo; chronic renal failure 115 aliskiren 94 placebo; renal failure 86 aliskiren, 66 placebo; acute renal failure 104 aliskiren, 83 placebo; acute pre-renal failure 5 aliskiren, 3 placebo; blood potassium increased 15 aliskiren, 8 placebo; dizziness 327 aliskiren, 314 placebo; postural dizziness 19 aliskiren, 13 placebo; syncope 73 aliskiren, 86 placebo; presyncope 13 aliskiren, 16 placebo; fall aliskiren, 123 placebo 113; orthostatic hypotension 55 aliskiren, 50 placebo; circulatory collapse 9 aliskiren, 7 placebo; hypovolemic shock 3 aliskiren, 2 placebo. Of these, adverse events leading to study drug discontinuation included: blood creatinine increased 16 aliskiren, 7 placebo; chronic renal failure 13 aliskiren 9 placebo; renal failure 11 aliskiren, 10 placebo; acute renal failure 5 aliskiren, 10 placebo; acute pre-renal failure 1 aliskiren, 0 placebo; blood potassium increased 2 aliskiren, 1 placebo; dizziness 4 aliskiren, 4 placebo; postural dizziness 0 aliskiren, 0 placebo; syncope 2 aliskiren, 1 placebo; presyncope 0 aliskiren, 0 placebo; fall aliskiren, 0 placebo 0;orthostatic hypotension 1 aliskiren, 2 placebo; circulatory collapse 1 aliskiren, 0 placebo; hypovolemic shock 2 aliskiren, 0 placebo. 28