Understanding the importance of blood pressure control An overview of new guidelines: How do they impact daily current management? Slides presented during CDMC in Almaty, Kazakhstan on Saturday April 12, 2014 and prepared by: Michael Weber, MD Professor of Medicine State University New York Downstate, College of Medicine, New York, NY, USA
Hypertension: 2014 Highlights of Hypertension Guidelines: Making the Most of Limited Evidence Michael A, Weber, MD Editor-in-Chief, The Journal of Clinical Hypertension, Professor of Medicine, Division of Cardiovascular Medicine, SUNY Downstate College of Medicine
Michael Weber, MD, Disclosures Research: Boston Scientific; Medtronics; Astra Zeneca Consulting: Medtronics, Novartis, Boehringer Ingelheim, Forest Speakers Programs: Arbor
Issues with contemporary guidelines Strong focus on evidence Belief that only prospectively defined primary endpoints from randomized, controlled, blinded clinical trials should be considered in decision-making As a result, only a very small fraction of available information can be used in making the guidelines Inevitably, many important issues that depend on other types of evidence, or the experience and judgment of experts, are now omitted
JNC 7: algorithm for the treatment of hypertension Lifestyle modifications Not at goal blood pressure (<140/90 mmhg) (<130/80 mmhg for those with diabetes or chronic kidney disease) Initial drug choices Without compelling indications With compelling indications Stage 1 hypertension (SBP 140 159 or DBP 90 99 mmhg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Stage 2 hypertension (SBP >160 or DBP >100 mmhg) 2 drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Not at goal blood pressure Drug(s) for the compelling indications* Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist *Compelling Indications Heart failure; post-mi; high coronary artery disease risk; diabetes; chronic kidney disease; recurrent stroke prevention Chobanian, AV et al. JAMA 2003;289:2560 2572
IHD mortality (Floating absolute risk and 95% CI) IHD mortality (Floating absolute risk and 95% CI) CHD rates by SBP, DBP and age 256 128 64 32 16 A: Systolic blood pressure Age at risk: 8 4 2 1 80 89 years 70 79 years 60 69 years 50 59 years 40 49 years B: Diastolic blood pressure Age at risk: 80 89 256 years 128 64 32 16 8 4 2 1 70 79 years 60 69 years 50 59 years 40 49 years 120 140 160 180 Usual systolic blood pressure (mmhg) 70 80 90 100 110 Usual diastolic blood pressure (mmhg) Adapted from Lewington et al. Lancet. 2002; 360:1903 1913
CV event rate (%) What made traditional antihypertensive therapy traditional: initial placebo-controlled VA studies 40 35 30 25 20 15 10 5 Placebo Active On assigned meds at study end: VA-1 92% VA-2 85% 0 VA-1 DBP 115 129 mmhg VA-2 DBP 90 114 mmhg Active treatment: HCTZ 50-100 mg, reserpine 0.1 0.2 mg, hydralazine 100 200 mg Veterans Administration Cooperative Study Group 1. JAMA 1967;202:116 122 Veterans Administration Cooperative Study Group 2. JAMA 1970;213:1143 1152
Systolic Hypertension in the Elderly Program (SHEP) Multicenter, randomized, double-blind, placebo-controlled, patients aged 60 years, systolic BPs >160 mmhg & diastolic BPs <90 mmhg, using 12.5-25 mg chlorthalidone + other drugs if needed (Starting SBP: 170 mmhg; achieved SBP: Placebo 155 mmhg, active treatment 143 mmhg) 10 Placebo (n=2371) Active treatment (n=2365) Cumulative fatal and nonfatal stroke rate per 100 participants 8 6 4 2 36% 0 0 12 24 36 48 60 Months 72 SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.
Systolic Hypertension in Europe Trial (Syst-Eur) Randomized, double-blind placebo trial of patients aged 60 years with isolated systolic hypertension, placebo vs nitrendipine 10-40 mg ± enalapril 5-20 mg ± HCTZ. Goal: Lower SBP by 20 mm Hg to <150 mm Hg: In reality, placebo = 161 mmhg; active = 151 mmhg Fatal and Nonfatal Strokes Fatal and Nonfatal Myocardial Infarction Events per 100 patients 6 5 4 3 2 1 42% reduction P=0.003 4 3 2 1 30% reduction P=0.12 0 0 0 1 2 3 4 Time since Randomization randomization (Yrs) (y) 0 1 2 3 4 Time since Randomization (Yrs) Time since randomization (y) Staessen JA et al. Lancet. 1997;350:757-764.
HYVET (Patients Aged >80): BP Effects During Trial Patients with isolated systolic hypertension; baseline SBP 174 mmhg; Target BP <150 mmhg; Achieved BP: placebo = 158 mmhg; active = 143 mmhg Blood pressure (mmhg) 180 170 160 150 140 130 120 110 100 90 80 70 15 mmhg 6 mmhg 0 1 2 3 4 5 Follow-up (years) Placebo Indapamide SR ± perindopril Median follow-up 1.8 years Beckett NS, et al. N Engl J Med 2008;358:1887 1998
HYVET: 21% reduction in total mortality with active treatment versus placebo p=0.019 Beckett NS, et al. N Engl J Med 2008;358:1887 1998
Effective blood pressure control can reduce cardiovascular risk* HR (95% CI) of CV events in patients being followed up to 6 years Fatal and non-fatal cardiac events Fatal and non-fatal stroke All-cause death Myocardial infarction Heart failure hospitalizations 0.75 (0.67 0.83) 0.55 (0.46 0.64) 0.79 (0.71 0.88) 0.86 (0.73 1.01) 0.64 (0.55 0.74) 0.6 0.8 1.0 1.2 SBP controlled at 6 months (n=10,755) SBP not controlled at 6 months (n=4,490) *Pooled analysis of patients enrolled in the VALUE trial; blood pressure control defined as SBP <140 mmhg Statistically significant difference (p<0.05) vs SBP not controlled at 6 months BP=blood pressure; CI=confidence interval; CV=cardiovascular; HR=hazard ratio; SBP=systolic blood pressure; VALUE=Valsartan Antihypertensive Longterm Use Evaluation 1. Weber MA, et al. Lancet 2004;363:2049-51.
Events per 1,000 patient-years Events per 1,000 patient-years Major Outcomes by Achieved Systolic Blood 28 Pressure Category in ACCOMPLISH (1) Primary Endpoint* Cardiovascular (CV) Death p-values versus >140 10 p-values versus >140 24 0.0007 <0.0001 <0.0001 NS 0.0008 0.0147 8 20 16 6 12 110 to <120 n=1329 120 to <130 n=3593 130 to <140 n=3429 >140 n=2354 Systolic Blood Pressure Category (mmhg) 4 110 to <120 n=1329 120 to <130 n=3593 130 to <140 n=3429 >140 n=2354 Systolic Blood Pressure Category (mmhg) * CV Death or Non-fatal MI or Non-fatal Stroke Weber et al. Amer J Med 2013; 126:501-508
Effects of intensive blood pressure control on cardiovascular events in type 2 diabetes mellitus: The Action to Control Cardiovascular Risk In Diabetes (ACCORD) blood pressure trial William C Cushman, MD, FACP, FAHA Veterans Affairs Medical Center, Memphis, TN For The ACCORD Study Group
ACCORD: mean systolic pressures in treatment groups with time SBP (mm Hg) 140 130 120 Average : 133.5 Standard vs 119.3 Intensive, delta = 14.2 Intensive Standard 110 100 N = 4382 4050 2391 359 0 1 2 3 4 5 6 7 8 Years Post-Randomization Mean number of medications Intensive: 3.2 3.4 3.4 3.5 3.5 3.5 3.4 3.4 Standard: 1.9 2.1 2.1 2.2 2.2 2.3 2.3 2.3 Number of patients Intensive: 2,174 2,071 1,973 1,792 1,150 445 156 156 Standard: 2,208 2,136 2,077 1,860 1,241 504 203 201 Data shown are mean ± 95% CI ACCORD study group. N Engl J Med 2010;362:1575 1585
Patients with Events (%) Patients with Events (%) ACCORD: primary outcome and total stroke Primary outcome (Nonfatal MI, nonfatal stroke or CVD death) Nonfatal stroke 20 HR = 0.89 95% CI (0.73-1.07) 20 HR = 0.59 95% CI (0.39-0.89) Intensive Standard 15 15 NNT for 5 years = 89 10 10 5 5 0 0 1 2 3 4 5 6 7 8 Years Post-Randomization 0 0 1 2 3 4 5 6 7 8 Years Post-Randomization ACCORD study group. N Engl J Med 2010;362:1575 1585
Blood pressure criteria Achieving SBP <160 mmhg is of benefit Achieving SBP <150 mmhg is also of benefit Achieving SBP <140 mmhg also appears to be justified (though evidence not as rigorous as for <150 mmhg) Achieving SBP <130 mmhg doesn t provide better outcomes, but appears safe. Is around 130 mmhg optimal? Achieving SBP <120 mmhg is beneficial only for stroke. The SPRINT study in the US is now examining this target in high risk non-diabetic patients
James PA, et al. JAMA. 2013 Dec 18. doi: 10.1001/jama.2013.284427. [Epub ahead of print].
Authors of JNC 8 Panel: Recommendation 1 In the general population aged 60 years or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 150 mmhg or higher or diastolic blood pressure (DBP) of 90 mmhg or higher and treat to a goal SBP lower than 150 mmhg and goal DBP lower than 90 mmhg. Strong Recommendation Grade A Note: This was one of only two of the nine recommendations of the panelists that claimed to be Strong and Grade A
How these concerns played out (1) The 150/90 mmhg threshold recommended by the panelists has been claimed to reduce the use of drugs and other resources and thus save money. But, if the generally-used 140/90 mmhg threshold is more correct, then these savings in money would be at the expense of increased major cardiovascular events particularly strokes - in the large high risk group of hypertensive people aged from 60 to 80.
How these concerns played out..(2) Following critiques of the panelists recommendation by external reviewers, the NHLBI (which was the original sponsor of the guidelines) announced it was quitting the guidelines business and handing it over to the AHA and the ACC. After reviewing the JNC panel s draft paper, the AHA and ACC also expressed concerns. After a failed negotiation the JNC panelists decided to simply publish their document independently, explicitly acknowledging that it is unsponsored by any federal agency or professional society.
Wright JT Jr, et al. Ann Intern Med. Published online 14 January 2014. doi: 10.7326/M13-2981.
Therapy Most evidence now supports 3 drug types: the RAS blockers (ACE inhibitors or ARBs); calcium channel blockers; and thiazide diuretics. Evidence for beta blockers weaker, except in HF, post-mi or angina Among the major classes, ethnicity, age and concomitant conditions will influence the selection of drugs Combination treatment is required in >50% of patients: most patients finish up with 2- or 3- drug combinations utilizing a RAS blocker, a calcium channel blocker and a thiazide From these 3 types of drugs, does it matter which are chosen for 2-drug combinations? For instance, is there a CV outcomes difference between the very popular RAS blocker/thiazide combination and a RAS blocker/calcium channel blocker combination?
Chlorthalidone (CLD) had positive effects on cardiovascular outcomes in landmark studies Clinical study Population studied and duration of study Comparators Significant findings HDFP 1 10,940 adults with HTN Over 5 years CLD Usual care CLD reduced mortality by 17% vs usual care MRFIT 2,3 12,866 high risk males with HTN Over 10.5 years CLD HCTZ Usual care CLD reduced mortality rate vs HCTZ CLD lowered risk for CV events by 21% vs HCTZ SHEP 4 4,736 adults >60 years of age with ISH Over 5 years CLD Placebo CLD lowered risk for CVD by 32% vs placebo ALLHAT 5 33,357 high risk adults with HTN Over 4.9 years CLD Amlodipine Lisinopril CLD was superior to amlodipine and lisinopril in prevention of CVD Recommend thiazide-type diuretics for first-line treatment of HTN ALLHAT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CLD=chlortalidone; CVD=cardiovascular disease; CV=cardiovascular; HCTZ=hydrochlorothiazde; HDFP=Hypertension Detection and Follow-up Program; HTN=hypertension; ISH=isolated systolic hypertension; MRFIT=Multiple Risk Factor Intervention Trial; SHEP=Systolic Hypertension in the Elderly Program 1. Hypertension Detection and Follow-up Program Cooperative Group. JAMA 1979;242:2562-71. 2. Multiple Risk Factor Intervention Trial Research Group. Circulation 1990;82:1616-28. 3. Dorsch MP, et al. Hypertension 2011;51:689-94. 4. SHEP Cooperative Research Group. JAMA 1991;265:3255-64 5. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA 2002;288:2981-97.
LIFE Trial: Losartan vs Atenolol Secondary Outcomes Reprinted from The Lancet, 359(9311), Dahlöf B et al, Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, 995-1003, 2002, with permission from Elsevier. Dahlöf B et al. Lancet 2002; 359: 995 1003.
Cumulative event rate ACCOMPLISH Kaplan-Meier curve for time to primary composite CV endpoint 0.16 0.12 Benazepril/amlodipine (552 patients with events: 9.6%) Benazepril/HCTZ (679 patients with events: 11.8%) 20% risk reduction* p=0.001 0.06 0.04 0 0 6 12 18 24 30 36 42 Time to first CV mortality/morbidity (months) Patients at risk (N) Benazepril/amlodipine 5,512 5,317 5,141 4,959 4,739 2,826 1,447 Benazepril/HCTZ 5,483 5,274 5,082 4,892 4,655 2,749 1,390 *Hazard ratio (95% confidence interval): 0.80 (0.72, 0.90) CV=cardiovascular; HCTZ=hydrochlorothiazide Jamerson K, et al. N Engl J Med 2008;359:2417 2428
Weber MA, et al. J Clin Hypertens (Greenwich). 2014 ; 16:14-26
Patient-type Black Patients (African Ancestry): All Ages White and Other Non-Black Patients: Younger than 60 White and Other Non-Black Patients: 60 Years and Older HYPERTENSION TREATMENT REGIMENS When Hypertension is the Only or Main Condition First Drug CCB* or thiazide diuretic Add Second Drug If Needed to Achieve a BP of <140/90 mmhg ARB** or ACE inhibitor (If unavailable can add alternative first drug choice) If Third Drug Needed to Achieve a BP of <140/90 mmhg Combination of CCB + ACE inhibitor OR ARB + thiazide diuretic ARB** or ACE Inhibitor CCB* or thiazide diuretic Combination of CCB + ACE inhibitor OR ARB + thiazide diuretic CCB* or thiazide diuretic (Although ACE inhibitors or ARBs are also usually effective) ARB** or ACE inhibitor (or CCB or thiazide if ACE inhibitor or ARB used first) Combination of CCB + ACE inhibitor OR ARB + thiazide diuretic BP, blood pressure; ARB, angiotensin receptor blocker; ACE, angiotensin converting enzyme; CCB, calcium channel blocker; egfr, estimated glomerular filtration rate * CCBs generally preferred, but thiazide may cost less. ** ARBs can be considered because ACE inhibitors can cause cough and angioedema, but ACE inhibitors may cost less. Weber MA, et al. J Hypertens. 2013;32:3 15. J Clin Hypertens. 2014; epub ahead of print.
Other Conditions HYPERTENSION TREATMENT REGIMENS When Hypertension is Associated With Other Conditions Hypertension AND Diabetes First Drug ARB or ACE inhibitor Note: in black patients, it is acceptable to start with CCB or thiazide Add Second Drug If Needed to Reach a BP of <140/90 mmhg CCB or thiazide diuretic Note: in black patients, if starting with CCB or thiazide, would now add ARB or ACE inhibitor ADD Third Drug If Needed to Reach a BP of <140/90 mmhg The alternative second drug (thiazide or CCB) Hypertension AND Chronic Kidney Disease ARB or ACE inhibitor Note: in black patients, good evidence for renal protective effects of ACE inhibitors CCB or thiazide diuretic The alternative second drug (thiazide or CCB) Hypertension AND Coronary Disease Hypertension AND Stroke History# Hypertension AND Heart Failure Beta blocker + ARB or ACE inhibitor CCB or thiazide diuretic The alternative second step drug (thiazide or CCB) ACE inhibitor or ARB Thiazide diuretic or CCB The alternative second drug (CCB or thiazide) Patients with symptomatic heart failure should receive an ARB or ACE inhibitor + beta blocker + diuretic + spironolactone regardless of blood pressure. Dihydropyridine CCB can be added if needed for BP control. BP=blood pressure; ARB=angiotensin receptor blocker; ACE=angiotensin converting enzyme; CCB=calcium channel blocker; CAD=Coronary Artery Disease; egfr=estimated glomerular filtration rate If egfr <40 ml/min, a loop diuretic, e.g. furosemide or torsemide, may be needed. NOTE: If previous myocardial infarction, a beta-blocker and ARB/or ACE inhibitor are indicated regardless of BP. # NOTE: When using a diuretic, evidence is strong for indapamide (if available). Weber MA, et al. J Clin Hypertens (Greenwich). 2013 Dec 17. J Hypertens. 2014;32:3 15.
Blood Pressure >140/90 in Adults Aged >18 years (For age >80 years, pressure >150/90 or >140/90 if high risk (diabetes, kidney disease) Start Lifestyle Changes (Lose weight, reduce dietary salt and alcohol, stop smoking) Start Drug Therapy (Consider a delay in uncomplicated Stage 1 patients)* Start Drug Therapy (In all patients) Stage 1 140-159/90-99* Stage 2 >160/100* Special Cases Black Patients Age <60 Years non-black Patients Age 60 Years All Patients Start With 2 Drugs Kidney disease Diabetes Coronary disease Stroke history Heart failure CCB or Thiazide If Needed, Add ACE-i or ARB OR combine CCB+Thiazide If Needed ACE-i or ARB If Needed, Add CCB or Thiazide If Needed CCB or Thiazide If Needed, Add ACE-i or ARB If Needed CCB or Thiazide + ACE-i or ARB If Needed * In stage 1 patients without other cardiovascular risk factors or abnormal findings, some months of regularly monitored lifestyle management without drugs can be considered. CCB+Thiazide+ACE-i (or ARB) If Needed, add other drugs e.g. spironolactone; centrally acting agents; β-blockers If Needed, Refer to a Hypertension Specialist CCB+Thiazide+ACE-i (or ARB) At any stage it is entirely appropriate to seek help from a hypertension expert if treatment is proving difficult. Weber MA, et al. J Clin Hypertens On-line 2013; Dec 17. J Hypertens. 2014;32:3 15.
Hypertension 2014 For most people, 140/90 mmhg defines hypertension and its treatment targets; for those aged >80, 150/90 mmhg is appropriate Patients with diabetes or kidney disease have the same BP criteria (140/90 mmhg) as other patients RAS blockers (ACE inhibitors or ARBs) and calcium channel blockers are emerging as preferred drugs, with thiazides to be used as CCB alternatives or as part of 3-drug regimens Treatment resistant hypertension is the current hot topic, but care should be taken not to over-diagnose this condition