Aortic dissection medical therapy

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Case #1


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Aarti Narayan, M.B.B.S [3]; Raviteja Guddeti, M.B.B.S. [4]

Overview

Type A dissections of the proximal aorta are generally managed with operative repair whereas Type B dissections of the descending aorta are generally managed medically. Even patients who are undergoing operative repair require optimal medical management. The two goals in the medical management of aortic dissection are to reduce blood pressure and to reduce the oscillatory shear on the wall of the aorta (the shear-force dP/dt or force of ejection of blood from the left ventricle). The target blood pressure should be a mean arterial pressure (MAP) of 60 to 75 mmHg.

Medical Therapy

Step 1: Urgent Surgical Consultation

  1. Simultaneous with the initiation of medical therapy as described below, urgent surgical consultation should be required regarding the potential need for operative repair of the dissection. Type A dissections of the proximal aorta are generally managed with operative repair whereas Type B dissections of the descending aorta are generally managed medically. Even patients who are undergoing operative repair require optimal medical management as described in the steps below.

Step 2: Rate Control

  1. The initial step in the medical management of the patient with aortic dissection is rate control. Rate control reduces oscillatory shear stress as well as blood pressure. Rate control should be accomplished before vasodilators are administered in so far as vasodilators can increase oscillatory shear stress.
  2. All patients should have an arterial line in the arm with the higher BP for accurate monitoring.
  3. Intravenous beta blockers can be administered and titrated to a heart rate of 60 bpm or less. The systolic blood pressure is kept at the lowest level that maintains adequate perfusion. Labetalol is an ideal agent in so far as it has both alpha and beta blocking properties. Initial treatment usually involves either labetalol (a 20 mg bolus followed by 20-80mg every 10 minutes to a total dose of 300 mg, or as an infusion of 0.5 to 2 mg/min) or Propranolol (1 to 10 mg load followed by 3mg/hr) with the goal being a heart rate of 60 beats per minutes. Lopressor can also be administered.
  4. If there is an absolute contraindication to the administration of beta blockers than a nondihydropyridine calcium channel–blocking can be administered as an alternative for rate control. The calcium channel blockers typically used are verapamil and diltiazem, because of their combined vasodilator and negative inotropic effects.
  5. If aortic insufficiency is present, then beta blocker administration should be undertaken carefully as prolonging the diastolic filling period may increase the magnitude of aortic regurgitation.
  6. Pain control with morphine is important in so far as it reduces sympathetic tone, heart rate and blood pressure.

Step 3: Blood Pressure Control

  1. Vasodilator administration should only be undertaken after the heart rate is controlled. If the heart rate is not controlled, the administration of vasodilators may cause reflex tachycardia, and cause further expansion of the dissection.
  2. If the systolic blood pressure remains above 120 mm Hg, then an angiotensin-converting enzyme inhibitor should be administered to further reduce the blood pressure. If this is ineffective, then the administration of parenteral vasodilators should be considered.
  3. If the heart rate is controlled, and the systolic blood pressure (SBP) is > 100 mmHg with adequate mentation and urine output, Sodium nitroprusside can be administered at a dose of 0.25 – 0.5 ug/kg/min. Nitroprusside should never be administered prior to beta blockade, as the hypotension can result in a reflex tachycardia.
  4. The target blood pressure should be a mean arterial pressure (MAP) of 60 to 75 mmHg.
  5. If the individual has refractory hypertension (persistent hypertension on the maximum doses of three different classes of antihypertensive agents), involvement of the renal arteries in the aortic dissection plane should be considered.

Step 4: Operative Repair Versus Medical Therapy

  1. Acute thoracic aortic dissection of the proximal ascending aorta (Type A dissections) should be urgently evaluated for emergent surgical repair given the increased risk of associated morbid/ mortal complications such as aortic rupture.
  2. Acute thoracic aortic dissection of the descending aorta (Type B dissection) should be managed medically unless and of the following morbid/ mortal complications develop:
  • For patients with DeBakey III or Daily B dissections, medical therapy offers an > 80% survival rate.

Step 5: Chronic Therapy

  1. In order to prevent recurrence and improve the patient's long term prognosis, smoking cessation, aggressive blood pressure control, and aggressive lipid- lowering therapy are essential. The relative risk of late rupture of an aortic aneurysm is 10 times higher in individuals who have uncontrolled hypertension, compared to individuals with a systolic blood pressure below 130 mmHg.

2022 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease[1]

Recommendations for Acute Medical Management of AAS Referenced studies that support the recommendations are summarized in the Online Data Supplement.

Class I
1. In patients presenting to the hospital with AAS, prompt treatment with anti-impulse therapy with invasive monitoring of BP with an arterial line in an ICU setting is recommended as initial treatment to decrease aortic wall stress.(Level of Evidence: B-NR)

2. Patients with AAS should be treated to an SBP <120 mm Hg or to lowest BP that maintains adequate end-organ perfusion, as well as to a target heart rate of 60 to 80 bpm.(Level of Evidence: C-LD) 3. In patients with AAS, initial management should include intravenous beta blockers, except in patients with contraindications.(Level of Evidence: B-NR)

4. In patients with AAS, initial management should include intravenous vasodilators if the BP is not well controlled after initiation of intravenous beta-blocker therapy.(Level of Evidence: C-LD) 5. Patients with AAS should be treated with pain control, as needed, to help with hemodynamic management.(Level of Evidence: C-EO)

Class IIa
In those with contraindications or intolerance to beta blockers, initial management with an intravenous non-dihydropyridine calcium channel blocker is reasonable for heart rate control.(Level of Evidence: B-NR)

2014 ESC Guidelines on the Diagnosis and Treatment of Aortic Diseases (DO NOT EDIT)[2]

General Consideration for Patients with Aortic Dissection (DO NOT EDIT)[2]

Class I
"1.Pain relief and blood pressure control is recommended for all patients with aortic dissection. (Level of Evidence: C)"

Treatment of Aortic Dissection Type A (DO NOT EDIT)[2]

Class I
"1.In type A of aortic dissection, urgent surgical intervention is recommended.(Level of Evidence: B)"[3][4]
Class IIa
"1.Hybrid approach is recommended in type A aortic dissection complicated with organ malperfusion.
a.Hybrid approach includes ascending aorta and/or arch replacement associated with any percutaneous aortic or branch artery procedure.(Level of Evidence: B)"[5][6][7][8][9][10]

Treatment of Aortic Dissection Type B (Uncomplicated) (DO NOT EDIT)[2]

Class I
"1.Medical therapy is always recommended for uncomplicated type B aortic dissection.(Level of Evidence: C)"
Class IIa
"1.Thoracic endovascular aortic repair should be considered for uncomplicated type B aortic dissection.(Level of Evidence: B)"[11][12]

Treatment of Aortic Dissection Type B (Complicated) (DO NOT EDIT)[2]

Class I
"1.For complicated type B aortic dissection, Thoracic endovascular aortic repair is recommended. (Level of Evidence: C)"
Class IIb
"1.Surgery may be considered for complicated type B aortic dissection. (Level of Evidence: C)"

2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease (DO NOT EDIT)[13]

Initial Management (DO NOT EDIT)[13]

Class I
"1. Initial management of thoracic aortic dissection should be directed at decreasing aortic wall stress by controlling heart rate and blood pressure as follows:
a. In the absence of contraindications, intravenous beta blockade should be initiated and titrated to a target heart rate of 60 beats per minute or less. (Level of Evidence: C)
b. In patients with clear contraindications to beta blockade, nondihydropyridine calcium channel–blocking agents should be utilized as an alternative for rate control. (Level of Evidence: C)
c. If systolic blood pressures remain greater than 120 mm Hg after adequate heart rate control has been obtained, then angiotensin-converting enzyme inhibitors and/or other vasodilators should be administered intravenously to further reduce blood pressure that maintains adequate end-organ perfusion. (Level of Evidence: C)
d. Beta blockers should be used cautiously in the setting of acute aortic regurgitation because they will block the compensatory tachycardia.[14] (Level of Evidence: C)"
Class III (Harm)
"1. Vasodilator therapy should not be initiated prior to rate control so as to avoid associated reflex tachycardia that may increase aortic wall stress, leading to propagation or expansion of a thoracic aortic dissection. (Level of Evidence: C)"

Definitive Management (DO NOT EDIT)[13]

Class I
"1. Urgent surgical consultation should be obtained for all patients diagnosed with thoracic aortic dissection regardless of the anatomic location (ascending versus descending) as soon as the diagnosis is made or highly suspected. (Level of Evidence: C)"
"2. Acute thoracic aortic dissection involving the ascending aorta should be urgently evaluated for emergent surgical repair because of the high risk of associated life-threatening complications such as rupture.[15] (Level of Evidence: B)"
"3. Acute thoracic aortic dissection involving the descending aorta should be managed medically unless life-threatening complications develop (e.g., malperfusion syndrome, progression of dissection, enlarging aneurysm, inability to control blood pressure or symptoms).[16][17][18][19][20][21] (Level of Evidence: B)"

Medical Treatment of Patients with Thoracic Aortic Diseases (DO NOT EDIT) [13]

Class I
"1. Stringent control of hypertension, lipid profile optimization, smoking cessation, and other atherosclerosis risk-reduction measures should be instituted for patients with small aneurysms not requiring surgery, as well as for patients who are not considered surgical or stent graft candidates. (Level of Evidence: A)"

Blood Pressure Control (DO NOT EDIT)[13]

Class I
"1. Antihypertensive therapy should be administered to hypertensive patients with thoracic aortic diseases to achieve a goal of less than 140/90 mm Hg (patients without diabetes) or less than 130/80 mm Hg (patients with diabetes or chronic renal disease) to reduce the risk of stroke, myocardial infarction, heart failure, and cardiovascular death.[22][23][24][25][26] (Level of Evidence: B)"
Class IIa
"1. An angiotensin receptor blocker (losartan) is reasonable for patients with Marfan syndrome, to reduce the rate of aortic dilatation unless contraindicated.[27][28] (Level of Evidence: B)"

Dyslipidemia Treatment (DO NOT EDIT)[13]

Class IIa
"1. Treatment with a statin to achieve a target LDL cholesterol of less than 70 mg/dL is reasonable for patients with a coronary heart disease risk equivalent such as non coronary atherosclerotic disease, atherosclerotic aortic aneurysm, and coexistent coronary heart disease at high risk for coronary ischemic events.[29][30][31][32] (Level of Evidence: A)"

Smoking Cessation (DO NOT EDIT)[13]

Class I
"1. Smoking cessation and avoidance of exposure to environmental tobacco smoke at work and home are recommended. Follow-up, referral to special programs, and/or pharmacotherapy (including nicotine replacement, buproprion, or varenicline) is useful, as is adopting a stepwise strategy aimed at smoking cessation (the 5 As are Ask, Advise, Assess, Assist, and Arrange).[33][34][35] (Level of Evidence: B)"

Aortic Arch and Thoracic Aortic Atheroma and Atheroembolic Disease (DO NOT EDIT)[13]

Class IIa
"1. Treatment with a statin is a reasonable option for patients with aortic arch atheroma to reduce the risk of stroke.[36] (Level of Evidence: C)"
Class IIb
"1. Oral anticoagulation therapy with warfarin (INR 2.0 to 3.0) or antiplatelet therapy may be considered in stroke patients with aortic arch atheroma 4.0 mm or greater to prevent recurrent stroke. (Level of Evidence: C)"

References

  1. ↑ Writing Committee Members. Isselbacher EM, Preventza O, Hamilton Black J, Augoustides JG, Beck AW; et al. (2022). "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines". J Am Coll Cardiol. doi:10.1016/j.jacc.2022.08.004. PMID 36334952 Check |pmid= value (help).
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwöger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, Allmen RS, Vrints CJ (November 2014). "2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC)". Eur. Heart J. 35 (41): 2873–926. doi:10.1093/eurheartj/ehu281. PMID 25173340.
  3. ↑ Sampson UK, Norman PE, Fowkes FG, Aboyans V, Yanna S, Harrell FE, Forouzanfar MH, Naghavi M, Denenberg JO, McDermott MM, Criqui MH, Mensah GA, Ezzati M, Murray C (March 2014). "Global and regional burden of aortic dissection and aneurysms: mortality trends in 21 world regions, 1990 to 2010". Glob Heart. 9 (1): 171–180.e10. doi:10.1016/j.gheart.2013.12.010. PMID 25432126. Vancouver style error: initials (help)
  4. ↑ Sampson, Uchechukwu K.A.; Norman, Paul E.; Fowkes, F. Gerald R.; Aboyans, Victor; Song, Yanna; Harrell, Frank E.; Forouzanfar, Mohammad H.; Naghavi, Mohsen; Denenberg, Julie O.; McDermott, Mary M.; Criqui, Michael H.; Mensah, George A.; Ezzati, Majid; Murray, Christopher (2014). "Estimation of Global and Regional Incidence and Prevalence of Abdominal Aortic Aneurysms 1990 to 2010". Global Heart. 9 (1): 159–170. doi:10.1016/j.gheart.2013.12.009. ISSN 2211-8160.
  5. ↑ Sampson UK, Norman PE, Fowkes FG, Aboyans V, Song Y, Harrell FE, Forouzanfar MH, Naghavi M, Denenberg JO, McDermott MM, Criqui MH, Mensah GA, Ezzati M, Murray C (March 2014). "Estimation of global and regional incidence and prevalence of abdominal aortic aneurysms 1990 to 2010". Glob Heart. 9 (1): 159–70. doi:10.1016/j.gheart.2013.12.009. PMID 25432125.
  6. ↑ Ius F, Fleissner F, Pichlmaier M, Karck M, Martens A, Haverich A, Shrestha M (November 2013). "Total aortic arch replacement with the frozen elephant trunk technique: 10-year follow-up single-centre experience". Eur J Cardiothorac Surg. 44 (5): 949–57. doi:10.1093/ejcts/ezt229. PMID 23660556.
  7. ↑ Subramanian S, Leontyev S, Borger MA, Trommer C, Misfeld M, Mohr FW (October 2012). "Valve-sparing root reconstruction does not compromise survival in acute type A aortic dissection". Ann. Thorac. Surg. 94 (4): 1230–4. doi:10.1016/j.athoracsur.2012.04.094. PMID 22748644.
  8. ↑ Shrestha M, Baraki H, Maeding I, Fitzner S, Sarikouch S, Khaladj N, Hagl C, Haverich A (January 2012). "Long-term results after aortic valve-sparing operation (David I)". Eur J Cardiothorac Surg. 41 (1): 56–61, discussion 61–2. doi:10.1016/j.ejcts.2011.04.012. PMC 3241084. PMID 21632258.
  9. ↑ Leontyev S, Borger MA, Etz CD, Moz M, Seeburger J, Bakhtiary F, Misfeld M, Mohr FW (December 2013). "Experience with the conventional and frozen elephant trunk techniques: a single-centre study". Eur J Cardiothorac Surg. 44 (6): 1076–82, discussion 1083. doi:10.1093/ejcts/ezt252. PMID 23677901.
  10. ↑ Murzi M, Tiwari KK, Farneti PA, Glauber M (July 2010). "Might type A acute dissection repair with the addition of a frozen elephant trunk improve long-term survival compared to standard repair?". Interact Cardiovasc Thorac Surg. 11 (1): 98–102. doi:10.1510/icvts.2010.235135. PMID 20395253.
  11. ↑ Nienaber CA, Rousseau H, Eggebrecht H, Kische S, Fattori R, Rehders TC, Kundt G, Scheinert D, Czerny M, Kleinfeldt T, Zipfel B, Labrousse L, Ince H (December 2009). "Randomized comparison of strategies for type B aortic dissection: the INvestigation of STEnt Grafts in Aortic Dissection (INSTEAD) trial". Circulation. 120 (25): 2519–28. doi:10.1161/CIRCULATIONAHA.109.886408. PMID 19996018.
  12. ↑ Nienaber CA, Kische S, Rousseau H, Eggebrecht H, Rehders TC, Kundt G, Glass A, Scheinert D, Czerny M, Kleinfeldt T, Zipfel B, Labrousse L, Fattori R, Ince H (August 2013). "Endovascular repair of type B aortic dissection: long-term results of the randomized investigation of stent grafts in aortic dissection trial". Circ Cardiovasc Interv. 6 (4): 407–16. doi:10.1161/CIRCINTERVENTIONS.113.000463. PMID 23922146.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE; et al. (2010). "2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine". Circulation. 121 (13): e266–369. doi:10.1161/CIR.0b013e3181d4739e. PMID 20233780.
  14. ↑ American College of Cardiology. American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Society of Cardiovascular Anesthesiologists. Bonow RO, Carabello BA, Chatterjee K; et al. (2006). "ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons". J Am Coll Cardiol. 48 (3): e1–148. doi:10.1016/j.jacc.2006.05.021. PMID 16875962.
  15. ↑ Hagan PG, Nienaber CA, Isselbacher EM; et al. (2000). "The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease". JAMA. 283 (7): 897–903. PMID 10685714. Unknown parameter |month= ignored (help)
  16. ↑ Mehta RH, O'Gara PT, Bossone E; et al. (2002). "Acute type A aortic dissection in the elderly: clinical characteristics, management, and outcomes in the current era". J. Am. Coll. Cardiol. 40 (4): 685–92. PMID 12204498. Unknown parameter |month= ignored (help)
  17. ↑ Suzuki T, Mehta RH, Ince H; et al. (2003). "Clinical profiles and outcomes of acute type B aortic dissection in the current era: lessons from the International Registry of Aortic Dissection (IRAD)". Circulation. 108 Suppl 1: II312–7. doi:10.1161/01.cir.0000087386.07204.09. PMID 12970252. Unknown parameter |month= ignored (help)
  18. ↑ Estrera AL, Miller CC, Safi HJ; et al. (2006). "Outcomes of medical management of acute type B aortic dissection". Circulation. 114 (1 Suppl): I384–9. doi:10.1161/CIRCULATIONAHA.105.001479. PMID 16820605. Unknown parameter |month= ignored (help)
  19. ↑ Umaña JP, Lai DT, Mitchell RS; et al. (2002). "Is medical therapy still the optimal treatment strategy for patients with acute type B aortic dissections?". J. Thorac. Cardiovasc. Surg. 124 (5): 896–910. PMID 12407372. Unknown parameter |month= ignored (help)
  20. ↑ Mehta RH, Suzuki T, Hagan PG; et al. (2002). "Predicting death in patients with acute type a aortic dissection". Circulation. 105 (2): 200–6. PMID 11790701. Unknown parameter |month= ignored (help)
  21. ↑ Chiappini B, Schepens M, Tan E; et al. (2005). "Early and late outcomes of acute type A aortic dissection: analysis of risk factors in 487 consecutive patients". Eur. Heart J. 26 (2): 180–6. doi:10.1093/eurheartj/ehi024. PMID 15618075. Unknown parameter |month= ignored (help)
  22. ↑ "Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)". JAMA. 288 (23): 2981–97. 2002. PMID 12479763. Unknown parameter |month= ignored (help)
  23. ↑ Hunt SA, Baker DW, Chin MH; et al. (2002). "ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary". J. Heart Lung Transplant. 21 (2): 189–203. PMID 11834347. Unknown parameter |month= ignored (help)
  24. ↑ Lewington S, Clarke R, Qizilbash N, Peto R, Collins R (2002). "Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies". Lancet. 360 (9349): 1903–13. PMID 12493255. Unknown parameter |month= ignored (help)
  25. ↑ Neal B, MacMahon S, Chapman N (2000). "Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration". Lancet. 356 (9246): 1955–64. PMID 11130523. Unknown parameter |month= ignored (help)
  26. ↑ Ogden LG, He J, Lydick E, Whelton PK (2000). "Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification". Hypertension. 35 (2): 539–43. PMID 10679494. Unknown parameter |month= ignored (help)
  27. ↑ Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC (2008). "Angiotensin II blockade and aortic-root dilation in Marfan's syndrome". N. Engl. J. Med. 358 (26): 2787–95. doi:10.1056/NEJMoa0706585. PMC 2692965. PMID 18579813. Unknown parameter |month= ignored (help)
  28. ↑ Lacro RV, Dietz HC, Wruck LM; et al. (2007). "Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome". Am. Heart J. 154 (4): 624–31. doi:10.1016/j.ahj.2007.06.024. PMC 3042860. PMID 17892982. Unknown parameter |month= ignored (help)
  29. ↑ Evans J, Powell JT, Schwalbe E, Loftus IM, Thompson MM (2007). "Simvastatin attenuates the activity of matrix metalloprotease-9 in aneurysmal aortic tissue". Eur J Vasc Endovasc Surg. 34 (3): 302–3. doi:10.1016/j.ejvs.2007.04.011. PMID 17574455. Unknown parameter |month= ignored (help)
  30. ↑ Leurs LJ, Visser P, Laheij RJ, Buth J, Harris PL, Blankensteijn JD (2006). "Statin use is associated with reduced all-cause mortality after endovascular abdominal aortic aneurysm repair". Vascular. 14 (1): 1–8. PMID 16849016.
  31. ↑ Kurzencwyg D, Filion KB, Pilote L; et al. (2006). "Cardiac medical therapy among patients undergoing abdominal aortic aneurysm repair". Ann Vasc Surg. 20 (5): 569–76. doi:10.1007/s10016-006-9078-z. PMID 16794911. Unknown parameter |month= ignored (help)
  32. ↑ Yilmaz MB, Biyikoglu SF, Guray Y; et al. (2004). "Level of awareness of on-treatment patients about prescribed statins". Cardiovasc Drugs Ther. 18 (5): 399–404. doi:10.1007/s10557-005-5065-9. PMID 15717143. Unknown parameter |month= ignored (help)
  33. ↑ Ockene IS, Miller NH (1997). "Cigarette smoking, cardiovascular disease, and stroke: a statement for healthcare professionals from the American Heart Association. American Heart Association Task Force on Risk Reduction". Circulation. 96 (9): 3243–7. PMID 9386200. Unknown parameter |month= ignored (help)
  34. ↑ Daly LE, Mulcahy R, Graham IM, Hickey N (1983). "Long term effect on mortality of stopping smoking after unstable angina and myocardial infarction". Br Med J (Clin Res Ed). 287 (6388): 324–6. PMC 1548591. PMID 6409291. Unknown parameter |month= ignored (help)
  35. ↑ "Quick reference guide for clinicians. Smoking cessation: information for specialists. U.S. Department of Health and Human Services". J Am Acad Nurse Pract. 8 (7): 317–22. 1996. PMID 9281974. Unknown parameter |month= ignored (help)
  36. ↑ Tunick PA, Nayar AC, Goodkin GM; et al. (2002). "Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque". Am. J. Cardiol. 90 (12): 1320–5. PMID 12480041. Unknown parameter |month= ignored (help)

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